Role of pharmacokinetics and metabolism in drug discovery and development

Pharmacological Reviews

Volumn 49, Issue 4, 1997, Pages 403-449

  Lin, Jiunn H ^a   Lu, Anthony Y H ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2,3 DIHYDRO 1 METHYL 2 OXO 5 PHENYL 1H 1,4 BENZODIAZEPIN 3 YL) 3 (3 METHYLPHENYL)UREA; 3 [4 METHOXYCARBONYL 4 (N PHENYLPROPIONAMIDO)PIPERIDINO]PROPIONIC ACID; 7 CHLORO 5,6 DIHYDRO 3 (5 ISOPROPYL 1,2,4 OXADIAZOL 3 YL) 5 METHYL 4H IMIDAZO[1,5 A][1,4]BENZODIAZEPIN 6 ONE; A 77003; A 80987; ATRACURIUM; BISPHOSPHONIC ACID DERIVATIVE; CARBIDOPA PLUS LEVODOPA; CHOLINESTERASE; CILASTATIN PLUS IMIPENEM; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DORZOLAMIDE; DRUG; DRUG METABOLITE; DRUG METABOLIZING ENZYME; IMIPENEM; INDINAVIR; PARACETAMOL; PHENACETIN; PRODRUG; PROTEINASE INHIBITOR; REMIFENTANIL; SEZOLAMIDE; SULINDAC; TIMOLOL MALEATE;

CLINICAL TRIAL; DRUG ABSORPTION; DRUG ACETYLATION; DRUG DESIGN; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG METABOLISM; DRUG OXIDATION; DRUG PROTEIN BINDING; DRUG RESEARCH; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; METHYLATION; NONHUMAN; ORAL DRUG ADMINISTRATION; PHARMACOGENETICS; PRIORITY JOURNAL; REVIEW; SEX DIFFERENCE; SPECIES DIFFERENCE; STEREOCHEMISTRY;

ANIMALS; DRUG DESIGN; DRUG TOXICITY; HUMANS; MODELS, BIOLOGICAL; PHARMACEUTICAL PREPARATIONS; PHARMACOGENETICS; PHARMACOKINETICS; SPECIES SPECIFICITY;

EID: 0031472588     PISSN: 00316997     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (494)

1. AARONS, L.: Kinetics of drug-drug interactions. In Pharmacokinetics: Theory and Methodology, ed. by M. Rowland and G. Tucker, pp. 163-186, Pergamon Press, New York, 1986.
2. AARONS, L. J., AND ROWLAND, M.: Kinetics of drug displacement interactions. J. Pharmacokint. Biopharm. 9: 181-190, 1981.
3. ABAS, A., AND MEFFIN, P. J.: Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs: IV - ketoprofen disposition. J. Pharmacol. Exp. Ther. 240: 637-641, 1987.
4. 1-acid glycoprotein. Clin. Pharmacol. Ther. 32: 652-658, 1982.
5. 1-acid glycoprotein by drugs. In Plasma Binding of Drugs and Its Consequences, ed. by F. Belpaire, M. Bogaert, J. P. Tillement, and R. Verbeeck, pp. 57-68, Academia Press, Ghent, Belgium, 1991.
6. ADAMS, S. S., BOUGH, R. G., CLLIFFE, E. E., DICKINSON, W., LESSEL, B., MCCULLOUGH, K. F., MILIS, R. F. N., NICHOLSON, J. S., AND WILLIAMS, G. A. H.: Some aspects of the pharmacology, metabolism and toxicology of ibuprofen. Rheumatol. Phys. Med. 10(suppl.): 9-26, 1970.
7. ADAMS, S. S., BRESLOFF, P., AND MANSON, C. G.: Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (-) isomer. J. Pharm. Pharmacol. 28: 256-257, 1976.
8. ADAMS, S. S., MCCULLOUGH, K. F., AND NICHOLSON, J. S.: The pharmacological properties of ibuprofen, an anti-inflammatory analgesic and antipyretic agent. Arch. Int. Pharmacodyn. Ther. 178: 115-129, 1969.
9. ALBERT, A.: Chemical aspects of selective toxicity. Nature (Lond.) 182: 421-426, 1958.
10. ALBERTS, A. W., CHEN, J., KURON, G., HUNT, V., HUFF, J., HOFFMAN, C., ROTHROCK, J., LOPEZ, M., JOSHUA, H., HARRIS, E., PATCHETT, A. A., MONAGHAN, R., CURRIE, S., STAPLEY, E., ALBERS-SCHONBERG, G., HENSENS, O., HIRSHFIELD, J., HOOGSTEEN, K., LIESCH, J., AND SPRINGER, J.: Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA 77: 3957-3961, 1980.
11. ALEXANDER, J., WALLIN, H., ROSSLAND, O. J., SOLBERG, K. E., HOLME, J. A., BECHER, G., ANDERSON, R., AND GRIVAS, S.: Formation of a glutathione conjugate and a semistable transportable glucuronide conjugate of N2-oxidized species of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine PhIP in rat liver. Carcinogenesis 12: 2239-2245, 1991.
12. ALVAN, G., BECHTEL, P., ISELIUS, L., AND GUNDERT-REMY, U.: Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur. J. Clin. Pharmacol. 39: 533-537, 1990.
13. AMIDON, G. L., SINKO, P. J., AND FLEISHER, D.: Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm. Res. 5: 651-654, 1988.
14. ANDERSSON, T., CEDERBERG, C., EDVARDSSON, G., HEGGELUND, A., AND LUNDBORG, P.: Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. Clin. Pharmacol. Ther. 47: 79-85, 1990.
15. ANDERRSON, T., REGÅRDH, C. G., LOU, Y. C., ZHANG, Y., DAHI., M., AND BERTILSSON, L.: Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics 2: 25-31, 1992.
16. ARENDT, R. M., GREENBLATT, D. J., DEJONE, R. H., AND SELLERS, E. M.: Benzodiazepine entry into CSF and brain: kinetic, dynamic and in vitro correlations. Clin. Pharmacol. Ther. 33: 239 (Abstract), 1983.
17. ARIËNS, E. J.: Excrusions in the field of SAR: a consideration of the past, the present and the future. In Biological Activity and Chemical Structure, ed. by J. A. Keverling Buisman, pp. 1-35, Elsevier, Amsterdam, 1972.
18. ARIËNS, E. J.: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur. J. Clin. Pharmacol. 26: 663-668, 1984.
19. ARIËNS, E. J.: Racemic therapeutics: problems all along the line. In Chirality in Drug Design and Synthesis, ed. by C. Brown, pp. 29-43, Academic Press, New York, 1990.
20. ARIËNS, E. J., AND SIMONIS, A. M.: Optimalization of pharmacokinetics: an essential aspect of drug development - by "metabolic stabilization". In Strategy in Drug Research, ed. by J. A. Keverling Buisman, pp. 165-178, Elsevier, Amsterdam, 1982.
21. ARROWSMITH, J. E., CAMPBELL, S. F., CROSS, P. E., STUBBS, J. K., BURGES, R. A., GARDINER, D. G., AND BLACKBURN, K. J.: Long acting dihydropyridine calcium antagonists: I - 2-Alkoxymethyl derivatives incorporating basic sub- stituents. J. Med. Chem. 29: 1696-1702, 1986.
22. ARTURSSON, P.: Epithelial transport of drugs: I - a model for studying the transport of drugs (β-blocking agents) over an intestinal epithelial cell line (Caco-2). J. Pharm. Sci. 79: 476-482, 1990.
23. ARTURSSON, P., AND KAKLSSON, J.: Correlation between drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 175: 880-885, 1991.
24. ARTURSSON, P., UNGELL, A-L., AND LÖFROTH, J. E.: Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm. Res. 10: 1123-1129, 1993.
25. ATKINSON, A. B., BROWN, J. J., LEVER, A. F., MCAREAVEY, D., ROBERTSON, J. I. S., BEHAN, P. O., MELVILLE, I. D., AND WEIR, A. I.: Neurological dysfunction in the two patients receiving captopril and cimetidine Lancet ii: 36-37, 1980.
26. ATKINSON, A. B., AND ROBERTSON, J. I. S.: Cuptopril in the treatment of clinical hypertension and cardiac failure. Lancet ii: 836-839, 1979.
27. AUNGST, B. J.: Novel formulation Strategies for improving oral bioavailability of drug with poor membrane permeation or presystemic metabolism. J. Pharm. Sci. 82: 979-987, 1993.
28. BÄÄRNHIELM, C., DAHLBÄCK, H., AND SKANBERG, I.: In vivo pharmacokinetics of felodipine predicted from in vitro studies in rat, dog and man. Acta. Phar- macol. Toxicol. 59: 113-122, 1986.
29. BÄÄRNHIELM, C., SKANBERG, I., AND BORG, K. O.: Cytochrome P-450-dependent oxidation of felodipine: a 1,4-dihydropyridine - to the correspnding pyridine. Xenobiotica 14: 719-726, 1984.
30. BAERTSCHI, S. W., RANEY, K. D., SHIMADA, T., HARRIS, T. M., AND GUENGERICH, F. P.: Comparison of rates of enzymatic oxidation of aflatoxin B1, aflatoxin G1 and sterigmatocystin and activation of the epoxides in forming gua- nyl-N7 adducts and inducing different gene responses. Chem. Res. Toxicol. 2: 114-122, 1989.
31. BAERTSCHI, S. W., RANEY, K. D., STONE, M. P. AND HARRIS, T. M.: Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1: the ultimate carcinogenic species. J. Am. Chem. Soc. 110: 7929-7931, 1988.
32. BAILLIE, T. A., AND DAVIS, M. R.: Mass spectrometry in the analysis of gluta- thione conjugates. Biol. Mass Spectrom. 22: 319-325, 1993.
33. BAILLIE, T. A., AND KASSAHUN, K.: Reversibility in glutathione-conjugate formation. Adv. Pharmacol. 27: 163-181, 1994.
34. BAILLIE, T. A., AND SLATTER, J. G.: Glutathione: a vehicle for the transport of chemically reactive metabolites in vivo. Acc. Chem. Res. 24: 264-270, 1991.
35. BALANI, S. K., ARISON, B. H., MATHAI, L., KAUFFMAN, L. R., MILLER, R. R., STEARNS, R. A., CHEN, I-W., AND LIN, J. H.: Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine. Drug Metab. Dispos. 23: 266-270, 1995.
36. BALDESSARINI, R. J.: Drugs and the treatment of psychiatric disorders. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed. by G. Gilman, L. S. Goodman, T. W. Rall, and I. Murad, pp. 383-435, Macmil- lan Publishing Co., New York, 1990.
37. BANDIERA, S.: Expression and catalysis of sex-specific cytochrome P-460 isozymes in rat liver. Can. J. Physiol. Pharmacol. 68: 762-768, 1990.
38. BARTH, N., ALAN, G., BORGÅ, O., AND SJÖQVIST, F.: Two-fold Interindividual variation in plasma protein binding of phenytoin in patients with epilepsy. Clin. Pharmacokinet. 1: 441-452, 1976.
39. BELL, D. R., PLANT, N. J., RIDER, C. G., NA, L.. BROWN, S., ATEITALLA, I., ACHARYA, S. K., DAVIES, M. H., ELIAS, E., AND JENKINS, R.: Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP 4A cDNAs. Biochem. J. 294: 173-180, 1993.
40. BERESFORD, A. P.: CYP 1A1: friend or foe? Drug Metab. Rev. 25: 503-517, 1993.
41. BERRY, M. N., HALLS, H. J., AND GRIVELL, M. B.: Techniques for pharmacological and toxicological studies with isolated hepatocyte suspensions. Life Sci. 51: 1-16, 1992.
42. BERTILSSON, L., BRAITHWAITE, T., TYBRING, G., GARLE, M., AND BORGA, O.: Techniques for plasma protein binding of demethylchlorimipramine. Clin. Pharmacol. Ther. 26: 265-271, 1979.
43. BERTILSSON, L., HENTHORN, T. K., SANZ, E., TYBRINH, G., SAWE, J., AND VILLÉN, T.: Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin hydroxylation pheno- type. Clin. Pharmacol. Ther. 45: 348-355, 1989.
44. BEVAN, D. R.: Prolonged mivacurium-induced neuromuscular block. Anesth. Analg. 77: 4-6, 1993.
45. BICKEL, M. H.: Factors affecting the storage of drugs and other xenobiotics in adipose tissue. In Advances in Drug Research, ed. by B. Testa, and U. Meyer, pp. 56-86, Academic Press, New York, 1994.
46. BLAINE E. H., FANELLI, G. M., JR., IRVIN, J. D., TOBERT, J. A., AND DAVIES, R. O.: Enantiomers of indacrinone: a new approach to producing an isouricemic diuretic. Clin. Exp. Hypertens. [A] 4: 161-176, 1982.
47. BLASCHKE, T. F.: Chromatographic resolution of racemates. Angew. Chem. Int. Ed. Engl. 19: 13-24, 1980.
48. BLASCHKE, T. F., KRAFT, H. P., FICKENTSCHER, K., AND KÖHLER, F.: Chromatographische racemattrennung von thalidomid und teratogene wirkung der enantiomere. Drug Res. 29: 1640-1642, 1979.
49. BLASCHKE, T. F., NIES, A. S., AND MAMELOK, R. D.: Principles of therapeutics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed. by A. F. Gilman, L. S. Goodman, T. W. Rall, and F. Murad, 7th ed., pp. 49-65, Macmillan Publishing Co., New York, 1985.
50. BLUM, M., GRANT, D. M., MCBRIDE, W., HEIM, M. AND MEYER, U. A.: Human arylamine N-acetyltransferase genes: isolation, chromosomal localization and function expression. DNA Cell Biol. 9: 193-203, 1990.
51. BLUM, M. R., LIAO, S. H. T., GOOD, S. S., AND DEMIRANDA, P.: Pharmacokinetics and bioavailability of zidovudine in man. Am. J. Med. 88: 189-196, 1988.
52. BOCK, K. W.: Metabolic polymorphisms affecting activation of toxic and muta- genic arylamines. Trends Pharmacol. Sci. 13: 223-226, 1992.
53. BOCK, K. W., AND LILIENBLUM, W.: Roles of uridine diphosphate glucuronosyl-transferase in chemical carcinogenesis. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 391-428, Springer-Verlag, Berlin, Germany, 1994.
54. BOCK, K. W., LIPP, H-P., AND BOCK-HENNIG, B. S.: Induction of drug-metabolizing enzymes by xenobiotics. Xenobiotica 20: 1101-111, 1990.
55. BODIN, N. O., EKSTRÖM, B., FORSGREN, U., JULAR, L. P., MAGNI, L., RAMSEY, C. H., AND SJOB̈ERG, B.: An orally well-absorbed derivative of ampicillin. Antimicrob. Agents Chemother. 8: 518-525, 1975.
56. BODOR, N.: Soft drugs: strategies for design of safer drugs. In Strategy in Drug Research, ed. by J. A. Keverling Buisman, pp. 137-164, Elsevier, Amsterdam, 1982.
57. BODOR, N.: Novel approaches to the design of safer drugs: soft drugs and site-specific chemical delivery systems. In Advances in Drug Research, ed. by B. Testa, pp. 255-331, Academic Press, New York, 1984.
58. BODOR, N., WOODS, R., RAPER, C., KEARNEY, P., AND KAMINSKI, J.: Soft drugs: 3 - a new class of anticholinergic agents. J. Med. Chem. 23: 474-480, 1980.
59. BOOBIS, A. R., SESARDIC, D., MURRAY, B. P., EDWARDS, R. J., SINGLETON, A. M., RICH, K. J., MURRAY, S., DE LA TORRE, R., SEGURA, J., PELKONEN, O., PASANEN, M., KOBAYASHI, S., ZHI-GUANG, T., AND DAVIES, D. S.: Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors. Xenobiotica 20: 1139-1161, 1990.
60. BOOKER, H. E., AND DARCEY, B.: Serum concentrations of free diphenylhydantoin and their relationships to clinical intoxication. Epilepsia 14: 177-184, 1973.
61. BOULENC, X., MARTI, E., JOYEUX, H., ROQUES, C., BERGER, Y., AND FABRE, G.: Importance of paracellular pathway for the transport of a new bisphosphonate using the human Caco-2 monolayers model. Biochem. Pharmacol. 46: 1591-1600, 1993.
62. BOXENBAUM, H.: Comparative pharmacokinetics of benzodiazepines in dog and man. J. Pharmacokinet. Biopharm. 10: 411-426, 1982.
63. BOXENBAUM, H., NEAFSEY, P. J., AND FOURNIER, D. J.: Hormesis, Gompetz functions and risk assessment. Drug Metab. Rev. 9: 195-229, 1988.
64. BOYD, M. R.: Evidence for the Clara cell as a site of cytochrome P-450-dependent mixed-function oxidase activity in lung. Nature (Lond.) 269: 713-717, 1977.
65. BOYD, M. R., AND BURKA, L. T.: In vivo studies on the relationship between target organ alkylation and pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanol. J. Pharmacol. Exp. Ther. 207: 687-697, 1978.
66. BRAY, K., AND QUAST, U.: Some degree of overlap exists between the K′-channels opened by cromakalim and those opened by minoxidil sulphate in rat isolated aorta. Naunyn-Schmeidbergs Arch. Pharmacol. 344: 351-359, 1991.
67. BREIMER, D. D.: Interindividual variations in drug disposition: clinical implications and methods of investigation. Clin. Pharmacokinet. 8: 371-377, 1983.
68. BRENDEL, K., FISHEK, R. L., KRUMDIECK, C. L., AND GANDOLFI, A. J.: Precision-cut rat liver slices in dynamic organ culture for structure-toxicity studies. J. Am. Coll. Toxicol. 9: 621-627, 1990.
69. BROLY, F., AND MEYER, U. A.: Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. Pharmacogenetics 3: 123-130, 1993.
70. BUCHERT, E., AND WOOSLEY, R. L.: Clinical implications of variable antiarrhythmic drug metabolism. Pharmacogenetics 2: 2-11, 1992.
71. BURCHELL, B., NEBERT, D. W., NELSON, D. R., BOCK, K. W., IYANAGI, T., JANSEN, P. L. M., LANCET, D., MULDER, G. J., CHOWDHURY, J. R., SIEST, G., TEPHLY, T. R., AND MACKENZIE, P. I.: The UDP-glucuronosyltransferae gene superfamily: suggested nomenclature based on evolutionary divergene. DNA Cell Biol. 10: 487-494, 1991.
72. BUREK, D. J., NITSCHKE, K. D., BELL, T. J., WACKERLE, D. L., CHILDS, R. C., BEYER, J. E., DITTENBER, D. A., RAMPY, L. W., AND MCKENNA, M. J.: Methylene chloride: a two year inhalation toxicity and oncogenicity study in rats and hamsters. Fundam. Appl. Toxicol. 4: 30-47, 1984.
73. BÜRKLE, H., DUNBAR, S., AND VAN AKEN, H.: Remifentanil: a novel, short-acting, μ-opioid. Anesth. Analg. 83: 646-651, 1996.
74. CACCIA, S., AND GARATTINI, S.: Formation of active metabolites of psychotropic drugs: an updated review of their significance. Clin. Pharmacokinet. 18: 434-459, 1990.
75. CALDWELL, J., WEIL, A., AND TANAKA, Y.: Species differences in xenobiotic conjugation. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 217-224, Taylor & Francis, London, UK, 1989.
76. CAMPBELL, D. B.: Stereoselectivity in clinical pharmacokinetics and drug development. Eur. J. Drug Metab. Pharmacokinet. 15: 109-125, 1990.
77. CASHMAN, J. R., YOUNG, Z., YANG, L., AND WRIGHTON, S. A.: Stereo- and regiosclective N- and S-oxidation of tertiary amines and sulfides in the presence of adult human liver microsomes. Drug Metab. Dispos. 21: 492-501, 1993.
78. CHADWICK, V. S., PHILLIPS, S. F., AND HOFMANN, A. F.: Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400); II - application to normal and abnormal permeability states in man and animals. Gastroenterology 73: 247-251, 1977.
79. CHAPMAN, D. E., CHRISTENSEN, T. A., MICHENER, S. R., AND POWIS, G.: Xenobiotic metabolism studies with human liver. In Human Drug Metabolism: From Molecular Biology to Man, ed. by E. H. Jeffery, pp. 53-63, CRC Press, Boca Raton, 1993.
80. CHEN, Z. R., SOMOGYI, A. A., AND BOCHNER, F.: Polymorphic O-demethylation of codeine. Lancet ii: 914-915, 1988.
81. CHIBA, M., FUJITA, S., AND SUZUKl, T.: Pharmacokinetic correlation between in vitro hepatic microsomal enzyme kinetics and in vivo metabolism of imipramine and desipramine in rats. J. Pharm. Sci. 79: 281-287, 1990.
82. CHIBA, M., HENSLEIGH, M., AND LIN, J. H.: Hepatic and intestinal metabolism of indinavir, a potent HIV protease inhibitor, in rat and human microsomes. Biochem. Pharmacol. 53: 1187-1195, 1997.
83. CHIBA, M., HENSLEIGH, M., NISHIME, J. A., BALANI, S. K., AND LIN, J. H.: Role of cytochromo P-450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab. Dispos. 24: 307-314, 1996.
84. CHIKHALE, E. G., NG, K-Y., BURTON, P. S., AND BORCHARDT, R. T.: Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides. Pharm. Res. 11: 412-419, 1994.
85. CHINJE, E., KENTISH, P., JARNOT, B., GEORGE, M., AND GIBSON, G.: Induction of the CYP 4A subfamily by perfluorodecanoic acid: the rat and the guinea pig as susceptible and non-susceptible species. Toxicol. Lett. 71: 69-75, 1994.
86. CHIU, S-H. L.: The use of in vitro metabolism studies in the understanding of new drugs. J. Pharmacol. Toxicol. Methods 29: 77-83, 1993.
87. CHOU, R. C., AND LEVY, G.: Effect of heparin or salicylate infusion on serum protein binding and on concentrations of phenytoin in serum, brain and cerebrospinal fluid of rats. J. Pharmacol. Exp. Ther. 210: 42-48, 1981.
88. CHRISTENSEN, L. K., HANSEN, J. M., AND KRISTENSEN, M.: Sulfaphenazole-induced hypoglycemic attacks in tolbutamide-treated diabetics. Lancet ii: 1298-1301, 1963.
89. CHRISTIAN, M. C., WITTES, R. E., LEYLAND-JONES, B., MCLEMORE, T. L., SMITH, A. C., GRIESHABER, C. K., CHABNER, B. A., AND BOYD, M. R.: 4-Ipomeanol: a novel investigational new drug for lung cancer. J. Natl. Cancer Inst. 81: 1155-1159, 1989.
90. CLARK, B., AND SMITH, D. A.: Pharmacokinetics and toxicity testing. Crit. Rev. Toxicol. 12: 343-385, 1984.
91. CLARKE, D. J., AND BURCHELL, B.: The uridine diphosphate glucuronosyltrans feruse multigene family: function and regulation. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 3-43, Springer-Verlag, Berlin, Germany, 1994.
92. CLAYTON, J. P., COLE, M., ELSON, S. W., AND FERRES, H.: BRL 8988 (talampicillin): a well absorbed oral form of apicillin. Antimicrob. Agents Chemother. 5: 870-671, 1974.
93. COLLIER, R., LINDUP, W. E., LIEBICH, H. M., AND SPITELLER, G.: Inhibitory effect of the uremic metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropaonic acid on plasma protein binding. Br. J. Pharmacol. 21: 610H-611P, 1986.
94. COMBALBERT, J., FABRE, I., FABRE, G., DALET, I., AND DERANCOURT, J.: Metabolism of cyclosporin A: IV - purification and identification of the rifampicin-inducible human liver cytochrome P-450 (Cyclosporin A oxidase) as a product of P-450 IIIA gene subfamily. Drug Metab. Dispos. 17: 197-207, 1989.
95. CONNEY, A. H., MILLER, E. C., AND MILLER, J. A.: The metabolism of methylated aminoazo dyes: V - evidence for induction of enzyme systems in the rat by 3-methyl-cholanthrene. Cancer Res. 16: 450-459, 1956.
96. CONNOR, A., ALTORKI, N., AND MOOSSA, A. R.: Tumors of colon, rectum and anus: clinical features and surgical treatment. In Comprehensive Textbook of Oncology, ed. by A. R. Moossa, M. C. Robson, and S. C. Schimpff, pp. 1063-1079, Williams and Wilkins, Baltimore, 1986.
97. CONRADI, R. A., HILGERS, A. R., HO, N. F. H., AND BURTON, P. S.: The influence of peptide structure on transport across Caco-2 cells. Pharm. Res. 8: 1453-1460, 1991.
98. CONRADI, R. A., HILGERS, A. R., HO, N. F. H., AND BURTON, P. S.: The influence of peptide structure on transport across Caco-2 cells: II - peptide bond modification which results in improved permeability. Pharm. Res. 9: 435-439, 1992.
99. COOK, C. S., KARIM, A., AND SOLLMAN, P.: Stereoselectivity in the metabolism of disopyramide enantiomers in rat and dog. Drug Metab. Dispos. 10: 116-121, 1982.
100. COUGLETRIE, M. W. H.: Role of molecular biology in the structural and functional characterization of the UDP-glucuronosyltransferases. In Progress in Drug Metabolism, ed. by G. G. Gibson, pp. 35-72, Taylor & Francis, London, UK, 1992.
101. COX, P. J., FARMER, P. B., FOSTER, A. B., GILBY, E. D., AND JARMAN, M.: The use of deuterated analogs in qualitative and quantitative investigations of the metabolism of cyclophosphamide (NSC-26271). Cancer Treat. Rep. 6: 483-491, 1976a.
102. COX, P. J., FARMER, P. B., JARMAN, M., JONES, M., STEC, W. J., AND KINAS, R.: Observations on the differential metabolism and biological activity of the optical isomers of cyclophosphamide. Biochem. Pharmacol. 25: 993-996, 1976b.
103. CREVELING, C. R., AND THAKKER, D. R.: O-, N- and S-methyltransferase. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 189-216, Springer-Verlag, Berlin, Germany, 1994.
104. CROUSE, R. G.: Human pharmacology of griseofulvin: the effect of fat intake on gastrointestinal absorption. J. Invest. Dermatol. 37: 529-532, 1961.
105. DAHL-PUUSTINEN, M-L., LIDEN, A., ALM, C., NORDIN, C., AND BERTILSSON, L.: Disposition of perphenazine is related to polymorphic debrisoquine hydroxylation in human beings, Clin. Pharmacol. Ther. 46: 78-81, 1989.
106. DEDRICK, R. L., FORRESTER, D. D., AND HO, D. H. W.: In vitro-in vivo correlation of drug metabolism: domination of 1-β-D-arabino-furano-sylcytosine, Biochem. Pharmacol. 21: 1-16, 1972.
107. DEVEREUX, T. R., JONES, K. G., BEND, J. R., FOUTS, Y. R., STATHAM, C. N., AND BOYD, M. R.: In vitro metabolic activation of pulmonary toxin 4-ipomeanol, in nonciliated bronchiolar epithelia (Clara) and alveolar type II cells isolated from rabbit lung. J. Pharmacol. Exp. Ther. 220: 223-227, 1982.
108. DIAZ, D., FAHRE, I., DAUJAT, M., SAINT AUBERT, B., BORIES, P., MICHEL, H., AND MAUREL, P.: Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P-450. Gastroenterology 99: 737-747, 1990.
109. DIGIOVANNA, J., BERRY, D. L., JUCHAU, M. R., AND SLAGA, T. J.: 2,3,7,8-tetrachlorodibenzo-p-dioxin: potent anticarcinogenic activity in CD-1 mice. Biochem. Biophys. Res. Commun. 86: 577-584, 1979.
110. DOGTEROM, P.: Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Dispos. 21: 699-704, 1993.
111. DOGTEROM, P., AND ROTHUIZEN, J.: A species comparison of tolbutamide metabolism in precision-cut liver slices from rats and dogs: qualitative and quantitative sex differences. Drug Metab. Dispos. 21: 705-709, 1993.
112. DÖHLER, K. D., WONG, C. C., AND VON ZUR MCHLEN, A.: The rat as model for the study of drug effects on thyroid function: consideration of methodological problems. Pharmacol. Ther. 5: 305-318, 1979.
113. DORSEY, B. D., LEVIN, R. B., MCDANlEL, S. L., VACCA, J. P., GUARE, J. P., DARKE, P. L., ZUGAY, J. A., EMINI, E. A., SCHLEIF, W. A., QUINTERO, J. C., LIN, J. H., CHEN, I-W., HOLLOWAY, M. K., FITZGERALD, P. M. D., AXEL, M. G., OSTOVIC, D., ANDERSON, P. S., AND HUFF, J. R.: L735 524: the design of a potent and orally bioavailable HIV protcase inhibitor. J. Med. Chem. 37: 3443-3451, 1994.
114. DOWNES, H., PERRY, R. S., OSTLUND, R. E., AND KARLER, R.: A study of the excitatory effects of barbiturates. J. Pharmacol. Exp. Ther. 175: 692-699, 1970.
115. DOWNES, H., AND WILLIAMS, J. K.: Effects of a convulsant barbiturate on the spinal monosynaptic pathway. J. Pharmacol. Exp. Ther. 168: 283-289, 1969.
116. DUGGAN, D. E.: Sulindac: therapeutic implications of the prodrug/pharmacophore equilibrium. Drug Metab. Rev. 12: 325-337, 1981.
117. DUGGAN, D. E., HOOKE, K. F., NOLL, R. M., AND KWAN, K. C.: Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem. Pharmacol. 24: 1749-1754, 1975.
118. DU SOUICH, P., AND BABINI, R.: Drug-plasma protein binding and apparent volume of distribution: a complex relationship. In Drug-Protein Binding, ed. by M. M. Reidenberg, and S. Erill, pp. 70-92, Praeger, New York, 1986.
119. 1-acid glycoprotein. In Plasma Binding of Drugs and Its Consequences, ed. by F. Belpaire, M. Bogaert, J. P. Tillement, and R. Verbeeck, pp. 69-82, Academia Press, Ghent, Belgium, 1991.
120. 1-acid glycoprotein) phenotying by use of immobilized pH gradients with 8 M urea and immunoblotting: a new variant encountered in a population study. Hum. Genet. 80: 183-185, 1988.
121. 1-acid glycoprotein. Clin. Pharmacol. Ther. 47: 338-346, 1990.
122. EKBLOM, M., HAMMARLUND-UDENAES, M., LUNDGRIST, T., AND SJOBERG, P.: Potential use of microdialysis in pharmacokinetics: a protein binding study. Pharm. Res. 9: 155-158, 1992.
123. EL MOUELHI, M., RUELIUS, H. W., FENSELAU, C., AND DULIK, D. M.: Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids: naproxen, ibuprofen and benoxaprofen. Drug Metab. Dispos. 15: 767-772, 1987.
124. ELSON, C. E., MALTZMAN, T. H., BOSTON, J. L., TANNER. M. A., AND GOULD, M. N.: Anticarcinogenic activity of d-limonene during the initiation and promotion/progression stages of DMBA-induced rat mammary carcinogenesis. Carcinogenesis 9: 331-332, 1988.
125. ERILL, S. R., CALVO, R., AND CARLOS, R.: Plasma protein carbamylation and decreased acidic drug protein binding in uremia. Clin. Pharmacol. Ther. 27: 612-618, 1980.
126. EVANS, D. A. P.: N-Acetyltransferase. Pharmacol. Ther. 42: 157-234, 1989.
127. EVANS, D. A. P.: N-acetylesterase. In Pharmacogenetics of Drug Metabolism, ed. by W. Kalow, pp. 96-178, Pergamon Press, New York, 1992.
128. EVANS, D. A. P., MANLEY, K. A., AND MCKUSICK, V. A.: Genetic control of isoniazid metabolism in man. Br. Med. J. 2: 485-491, 1960.
129. FABRO, S., SMITH, R. L., AND WILLIAMS, R. T.: Toxicity and teratogenicity of optical isomers of thalidomide. (Comment) Nature (Lond.) 215: 296, 1967.
130. FELDMAN, P. L., JAMES, M. K., BRACKEEN, M. R., BILOTTA, J. M., SCHUSTER, S. V., LAHEY, A. P., LUTZ, M. W., .JOHNSON, M. R., AND LEIGHTON, H. F.: Design, synthesis and pharmacological evaluation of ultrashort-to-long-acting opioid analgetics. J. Med. Chem. 34: 2202-2208, 1991.
131. FENSELAU, C.: Tandem mass spectrometry: the competitive edge for pharmacology. Annu. Rev. Pharmacol. Toxicol. 32: 555-578, 1992.
132. FICHTL, B., NIECIKCKI, A. V., AND WALTER, K.: Tissue binding versus plasma binding of drugs: general principles and pharmacokinetic consequences. In Advances in Drug Research, ed. by B. Testa, vol. 20, pp. 117-166, Academic Press, New York, 1991.
133. FIRST, M. R., WEISKITTEL, P., ALEXANDER, J. W., SCHROEDER, T. J., AND MYRE, S. A.: Concomitant administration of cyclosprin and ketoconazole in renal transplant recipients. Lancet ii: 1198-1201, 1984.
134. FLEISCH, H.: Adverse events. In Bisphosphonates in Bone Disease: From the Laboratory to the Patients, ed. by H. Fleisch, pp. 126-132, Stämpfl Co., Ltd., Berne, Switzerland, 1993.
135. FLEISCH, H., AND RUSSELL, R. G. G.: Pyrophosphate and pulyphosphate. In Pharmacology of the Endocrine System and Related Drugs, ed. by H. Hellar, and B. Pickering, pp. 61-100, Pergamon Press, New York, 1970.
136. FLEISCH, H., RUSSELL, K. G. G., BISAZ, S., CASEY, P. A., AND MÜHLBAUEK, R. C.: The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcif. Tissue Res. 2(suppl.): 10-10A, 1968.
137. FLEISCH, H., RUSSELL, R. G. G., AND FRANCIS, M. D.: Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science (Wash. DC) 165: 1262-1264, 1969.
138. FLEISCH, H., RUSSELL, R. G. G., AND STRAUMANN, F.: Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature (Lond.) 212: 901-903, 1966.
139. FLOWER, R. J., MONCADA, S., AND VANE, J. R.: Analgesic-antipyretics and anti-inflammatory agents: drugs employed in the treatment of gout. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed. by A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad, pp. 674-715, Macmillan Publisher, Inc., New York, 1985.
140. FOSTER, R. T., AND JAMALI, F.: Stereoselective pharmacokinetics of ketoprofen in the rat: influence of route of administration. Drug Metab. Dispos. 16: 623-626, 1988.
141. 1-acid glycoprotein in normal subjects and cardiac patients. Clin. Pharmacol. Ther. 36: 670-674, 1984.
142. GAN, L-S., Hsyu, P-H., Pritchard, J. F., and Thakker, D.: Mechanism of intestinal absorption ranitidine and Ondansetron: transport across Caco-2 cell monolayers. Pharm, Res. 10: 1722-1725, 1993.
143. GELBOIN, H. V.: Benzol(a)pyrene metaboloism, activation and carcinogenesis: role of mixed function oxidases and related enzymes. Pharmacol. Rev. 60: 1107-1166, 1980.
144. GERHARDT, R. E., KNOUSS, R. F., THYRUM, P. T., LUCHI, R. J., AND MORRIS, J. J.: Quinidine excretion in aciduria and alkaluria. Ann. Intern. Med. 71: 927-933, 1969.
145. GILLETTE, J. R.: Problems in correlating in vitro and in vivo studies of drug metabolism. In Pharmacokinetics: A Modern View, ed. by L. Z. Benet, G. Levy, and B. L. Ferraiolo, pp. 235-252, Plenum Press, New York, 1984.
146. GILLETTE, J. R.: Problems in extrapolations from animals to man. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 209-216, Taylor & Francis, London, UK, 1989.
147. GLASS, P. S. A.: Remifentanil: a new opioid. J. Clin. Anesth. 7: 556-563, 1995.
148. GONZALEZ, F. J., CRESPI, C. L., AND GELBOIN, H. V.: cDNA-expressed human cytochrome P-450s: a new age of molecular toxicology and human risk assessment. Mutat. Res. 247: 113-127, 1991.
149. GONZALEZ, F. J., AND NEBERT, D. W.: Evolution of the P450 gene superfamily: animal-plant "warfare", molecular drive and human genetic differences in drug metabolism. Trends Genet. 6: 182-187, 1990.
150. GOOD, S. S., DURACK, D. T., AND DEMIRANDA, P.: Biotransformation in various species and in humans of 3′-azido-3′-deoxythymidine, a potential agent for the treatment of AIDS. Fed. Proc. 45: 44-52, 1986,
151. GOUDSOUZIAN, N. G., D'HOLLANDER, A. A., AND VIBY-MOGENSEN, J.: Prolonged neuromuscular block from mivacurium in two patients with cholinesterase deficiency. Anesth. Analg. 77: 183-185, 1993.
152. GRANT, D. M., BLUM, M., BEER, M., AND MEYER, U. A.: Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Mol. Pharmacol. 39: 184-191, 1991.
153. GRASS, G. M., AND SWEETANA, S. A.: In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res. 5: 372-376, 1988.
154. GREEN, T.: Changes in metabolism during toxicity tests. Xenobiotica 20: 1233-1240, 1990.
155. GREEN, T.: Species differences in carcinogenicity: the role of metabolism and pharmacokinetics in risk assessment. Ann. Ist. Super. Sanita 27: 595-600, 1991.
156. GREENBLATT, D. J., ARENDT, R. M., ABERNATHY, D. K., GILES, H. G., SELLERS, E. M., AND SHADER, R. I.: In vitro quantitation of benzodiazepine lipophilicity: relation to in vivo distribution. Br. J. Anaesth. 55: 985-1089, 1983.
157. GREGORY, A. R.: Species comparisons in evaluating carcinogenicity in humans. Regul. Toxicol. Pharmacol. 8: 160-190, 1988.
158. GROEN, K., WARRANDER, A., MILES, G. S., BOOTH, B. S., AND MULDER, G. J.: Sulphation and glucuronidation of Xamoterol in the dog: dose dependence and site of Bulphation. Xenobiotica 18: 511-518, 1988.
159. GUENGERICH, F. P.: Oxidation of quinidino by human liver cytochrome O-450. Mol. Pharmacol. 30: 287-295, 1986.
160. GUENGERICH, F. P.: Mammalian Cytochrome P-450, pp. 1-201, vol. 1, CRC Press, Boca Raton, FL, 1987.
161. GUENGERICH, F. P., AND SHIMADA, T.: Human cytochrome P-450 enzymes and chemical carcinogenesis. In Human Metabolism: From Molecular Biology to Man, ed. by E. H. Jeffery. pp. 5-12, CRC Press, Boca Raton, FL, 1993.
162. GUGLER, R., AND JENSEN, J. C.: Drug-protein binding in liver disease and in patients with hypoalbuminemia. In Drug-Protein Binding, ed. by M. M. Reidenberg, and S. Erill, pp. 189-200, Praeger, New York, 1986.
163. GUILLOUZO, A., MOREL, F., FARDEL, O., AND MEUNIER, B.: Use of human hepatocyte cultures for drug metabolism studies. Toxicology 82: 209-219, 1993.
164. HAEFELY, W., KYBURZ, E., GERECKE, M., AND MÖHLER, H.: Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. In Advances in Drug Research, ed. by B. Testa, pp. 166-299, Academic Press, New York, 1985.
165. HAMMAN, M. A., WRIGHTON, S. A., AND HALL, S. D.: Sulindac metabolism by human liver microsomes. International Society for the Study of Xenobiotics Proceedings 6: 251, 1994.
166. p, f) of quinidine in rats. J. Pharm. Pharmacol. 36: 340-342, 1984.
167. HARD, G. C., AND WHYSNER, J.: Risk assessment of d-limonene: an example of male rat-specific renal tumorigens. Crit. Rev. Toxicol. 24: 231-254, 1994.
168. HARRIS, H. W.: High dose isoniazid compared with standard-dose isoniazid with PAS in the treatment of previously untreated cavitary pulmonary tuberculosis. In Transactions of the 20th Conference of Chemotherapy and Tuberculosis, pp. 39-68, U. S. Veterans Administation Army Navy, Washington, DC, 1961.
169. HARTRICK, C. T., DIRKES, W. E., COYLE, D. E., RAJ, P. R., AND DENSON, D. D.: Influence of bupivacaine on mepivacaine protein binding. Clin. Pharmacol. Ther. 36: 546-550, 1984.
170. HASSEN, H. P., AGARWAL, D. P., GOEDDE, H. W., BUCHER, H., HULAND, H., BRACHMANN, W., AND OVENBECK, R.: Association of N-acetyltransferase polymorphism and environmental factors with bladder carcinogens. Eur. Urol. 11: 263-266, 1985.
171. HAWKINS, D., PINKARD, R. N., AND FARR, R. S.: Acetylation of human serum albumin by acetylsalicylic acid. Science (Wash. DC) 160: 780-781, 1968.
172. HENDERSON, C. J., AND WOLF, C. R.: Molecular analysis of cytochrome P450s in the CYP2 gene family. In Progress in Drug Metabolism, ed. by G. G. Gibson, pp. 73-139, Taylor & Francis, London, UK, 1992.
173. HERRERA, A. M., SCOTT, D. O., AND LUNTE, C. E.: Microdialysis sampling for determination of plasma protein binding of drugs. Pharm. Res. 7: 1077-1081, 1990.
174. HIDALGO, I. J., RAUB, T. J., AND BORCHARDT, R. T.: Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96: 736-749, 1989.
175. Ho, N. F. H., MERKLR, H. P., AND HIGUCHI, W. I.: Quantitative, mechanistic and physiologically realistic approach to the biopharmaceutical design of oral drug delivery system. Drug Dev. Ind. Pharm. 9: 1111-1184, 1983.
176. HONIG, P. K., WOOSLEY, R. L., ZAMANI, K., CONNER, D. P., AND CANTILENA, L. R.: Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin. Pharmacol. Ther. 52: 231-238, 1992.
177. HONIG, P. K., WORTHAM, D. C., ZAMANI, K., CONNER, D. P., MULLIN, J. C., AND CANTILENA, L. R.: Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 269: 1535-1539, 1993.
178. HOSOKAWA, M., MAKI, T., AND SATOH, T.: Multiplicity and regulation of liver microsomal carboxylesterase in rats. Mol. Pharmacol. 31: 579-584, 1987.
179. HOSOKAWA, M., MAKI, T., AND SATOH, T.: Characterization of molecular species of liver microsomal carboxylesterases of several animal species and human. Arch. Biochem. Biophys. 277: 219-227, 1990.
180. HOUSTON, J. B.: Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47: 1469-1479, 1994.
181. HUANG, J. D., AND ØIE, S.: Effect of altered disapyramide binding its pharmacologic response in rabbits. J. Pharmacol. Exp. Ther. 223: 469-471, 1982.
182. HUANG, M-T., CHANG, R. L., FORTNER, J. G., AND CONNEY, A. H.: Studies on the mechanism of activation of microsomal benzo[a]pyrene hydroxylation by flavonoids. J. Biol. Chem. 256: 6829-6836, 1981.
183. HUGHES, R., AND CHAPPLE D. J.: The pharmacology of atracurium: a new competitive neuromuscular blocking agent. Br. J. Anaesth. 53: 31-44, 1981.
184. HUMPHREY, M. J.: Pharmacokinetic studies in the selection of new drugs: a case history on dihydropyridine calcium channel blockers. In Xenobiotic Metabolism and Disposition, ed. by R. (Kato, R. W. Estahrook, and M. N. Gayen, pp. 245-253, Taylor & Francis, New York, 1989.
185. HUNT, C. M., WESTERKAM, W. R., AND STAVE, G. M.: Effect of age and gender on the activity of human hepatic CYP3A. Biochem. Pharmacol. 44: 275-283, 1992.
186. HUTT, A. J., AND CALDWELL, J.: The metabolic chiral inversion of 2-arylpropionic acids: a novel route with pharmacological consequences. J. Pharm. Pharmacol. 38: 693-704, 1983.
187. IGARI, Y., SUGIYAMA, Y., AWAZU, S., AND HANANO, M.: Comparative physiologically based pharmacokinetics of hexobarbital, phenobarbital and thiopental in the rat. J. Pharmacokinet. Biopharm. 10: 53-75, 1982.
188. INABA, T., TAIT, A., NAKANO, M., MAHON, W. A., AND KALOW, W.: Metabolism of diazepam in vitro by human liver: independent variability of N-demethylation und C3-hydroxylation. Drug Metab. Dispos. 16: 605-608, 1988.
189. IOANNIDES, C., AND PARKE, D. V.: Induction of cytochrome P-4501 as an indicator of potential chemical carcinogenesis. Drug Metab. Rev. 25: 485-501, 1993.
190. IOANNIDES, C., SWEATMAN, B., RICHARDS, R., AND PARKE, D. V.: Drug metabolism in the ferret: effects of age, sex and strain. Gen. Pharmacol. 8: 243-249, 1977.
191. 1-acid glycoprotein. Clin. Pharmacol. Ther. 83: 255-258, 1983.
192. IWATSUBO, T., HIROTA, N., OOIE, T., SUZUKI, K., SHIMADA, N., CHIBA, K., ISHIZAK, T., GREEN, C. E., TYSON, C. A., AND SUGIYAMA, Y.: Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol. Ther., in press, 1997.
193. IYER, R. S., COLES, B. F., RANEY, K. D., THIER, R., GUENGERICH, F. P., AND HARRIS, T. M.: DNA adduction by the potent carcinogen aflatoxin B1: mechanistic studies. J. Am. Chem. Soc. 116: 1603-1609, 1994.
194. JACKSON, M. J.: Drug transport across gastrointestinal epithelia. In Physiology of the Gastrointestinal Tract, 2nd ed., ed. by L. R. Jackson, pp. 1597-1621, Raven Press, New York, 1987.
195. JAMALI, F., BERRY, B. W., TEHRANI, M. R., AND RUSSELL, S. A.: Stereoselective pharmacokinetics of flurbiprofen in humans and rats. J. Pharm. Sci. 77: 666-669, 1988.
196. JAMALI, F., MEHVAR, R., AND PASUTTO, F. M.: Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J. Pharm. Sci. 78: 695-715. 1989.
197. JENSEN, C. B., AND JOLLOW, D. J.: The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. Toxicol. Appl. Pharmacol. 111: 1-12, 1991.
198. JERINA, D. M., YAGI, H., THAKKER, D. R., KARLE, J. M., BUENING, M., CHANG, K. L., LEVIN, W., AND CONNEY, A. H.: Stereoselective metabolic activation of polycyclic aromatic hydrocarbons. In Advances in Pharmacology and Therapeutics, ed. by Y. Cohen, vol. 9, pp. 53-62, Pergamon Press, New York, 1979.
199. JEZEQUEL, S. G.: Central nervous system penetration of drugs: importance of physicochemical properties. In Progress in Drug Metabolism, ed. by G. G. Gibson, vol. 13, pp. 141-178, Taylor & Francis, London, UK, 1992.
200. JOHNSON, E. J., PALMEK, C. N. A., GRIFFIN, K. J., AND HSU.: M. H.: Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation. FASEB J. 10: 1241-1248, 1996.
201. JOHNHSON, G., JORDO, L., LUNDBORG, P., REGÅRDH, C. G., AND RÖNN, O.: Plasma levels and pharmacological effects of metoprolol administered as controlled release (Durules) and ordinary tablets in healthy volunteers. Int. J. Clin. Pharmacol. Ther. Toxicol. 18: 292-297, 1980.
202. JUMARIE, C., AND MALO, C.: Caco-2 cells culture in serum-free medium as a model for the study of enterocytic differentiation in vitro. J. Cell. Physiol. 149: 24-33, 1991.
203. KADLUBAR, F. F., MILLER, J. A., AND MILLER, E. C.: Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis. Cancer Res. 37: 805-814, 1977.
204. KADLUHAR, F. F., UNRUH, L. E., FLAMMANG, T. J., SPARKS, D., MITCHUM, R. K., AND MULDER, G. J.: Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion. Chem. Biol. Interact. 33: 129-147, 1981.
205. KALOW, W., AND BERTILSSON, L.: Interethnic factors affecting drug response. In Advances in Drug Research, ed. by B. Testa and U. A. Meyer, pp. 1-53, Academic Press, New York, 1994.
206. KALOW, W., AND GENEST, K.: A method for the detection of atypical forms of human serum cholinesterase: determination of dibucaine numbers. Can. J. Biochem. Physiol. 35: 339-346, 1957.
207. KAMATAKI, T.: Molecular toxicology of cytochrome P-450: focusing on interspecies homology. Yukugaku Zasshi 115: 370-377, 1995.
208. KANERVA, R. L., RIDDER, G. M., LEFEVER, F. R., AND ALDEN, C. L.: Comparison of short-term renal effects due to oral administration of decalin or d-limonene in young adult male Fischer 344 rats. Food Chem. Toxicol. 25: 345-354, 1987.
209. KAPPAS, A., ALVARES, A. P., ANDERSON, K. E., PANTUCK, E. J., PANTUCK, C. B., CHANG, R., AND CONNEY, A. H.: Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Clin. Pharmacol. Ther. 23: 445-450, 1978.
210. KAPPAS, A., ANDERSON, K. E., CONNEY, A. H., AND ALVARES, A. P.: Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin. Pharmacol. Ther. 20: 643-653, 1976.
211. KATO, R., AND YAMAZOE, Y.: Sex-dependent regulation of cytochrome P-450 expression. In Principles, Mechanisms and Biological Consequences of Induction, ed. by K. Ruckpaul and H. Rein, pp. 82-112, Taylor & Francis, New York, 1990.
212. KATO, R., AND YAMAZOE, Y.: The importance of substrate concentration in determining cytochrome P-450 therapeutically relevant in vivo. Pharmacogenetics 4: 359-362, 1994.
213. KAUMEIER, S.: The effect of the composition of food on the absorption of sulfameter. Int. J. Clin. Pharmacol. Biopharm. 17: 260-263, 1979.
214. KAWASAKI, S., SUGIYAMA, Y., IGA, T., HANANO, M., SANJO, K., BEPPU, T., AND IDEZUKI, Y.: Pharmacokinetic study on the hepatic uptake of indocyanine green in cirrhotic patients. Am. J. Gastroenterol. 80: 801-806, 1985.
215. KEATES, E. U., AND STONE, R.: The effect of d-timolol on intraocular pressure in patients with ocular hypertension. Am. J. Ophthalmol. 98: 73-78, 1984.
216. KELLY, J. G., AND O'MALLEY, K.: Clinical pharmacokinetics of the newer ACE inhibitors: a review. Clin. Pharmacokinet. 19: 177-196, 1990.
217. KEMPF, D. J., MARCH, K. C., DENISSEN, J. F., MCDONALD, E., VASAVANONDA, S., FLENTGE, C. A., GREEN, B. E., FINO, L., PARK, C. H., LONG, X-P., WIDEBURG, N. E., SALDIVAR, A., RUIZ, L., KATI, W. M., SHAM, H. L., ROBINS, T., STEWART, K. D., HSU, A., PLATTNER, J. J., LEONARD, J. M., AND NORBECK, D. W.: ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. USA 92: 2484-2488, 1995.
218. 2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. Antimicrob. Agents Chemother. 35: 2209-2214, 1991.
219. KLEINBLOESEM, C. H., VAN BRUMMELEN, P., FABER, H., DANHOF, M., VERMEULEN, N. Y., AND BREIMER, D. D.: Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochem. Pharmacol. 33: 3721-3724, 1984.
220. KOBAYASHI, S., MURRAY, S., WATSON, D., SESARDIC, D., DAVIES, D. S., AND BOOBIS, A. R.: The specificity of inhibition of debrisoquine 4-hydroxylase activity in quinidine and quinine in the rat is the reverse of that in man. Biochem. Pharmacol. 38: 2795-2799, 1989.
221. KOBLIAKOV, V., POPOVA, N., AND ROSSI, L.: Regulation of the expression of the sex-specific isoforms of cytochrome P-450 in rat liver. Eur. J. Biochem. 196: 585-591, 1991.
222. KOCH-WESER, J.: The serum level approaches to individualization of drug dosage. Eur. J. Clin. Pharmacol. 9: 1-8, 1975.
223. KOIKE, Y., MAGNUSSON, A., STEINER, E., RANE, A., AND SJOGVIST, F.: Ultrafiltration compared with equilibrium dialysis in determination of unbound phenytoin in plasma. Ther. Drug Monit. 7: 461-465, 1985.
224. KRAGH-HANSEN, U., BRENNAN, S. O., GALLIANO, M., AND SUJITA, O.: Binding of warfarin, salicylate and diazepam to genetic variants of human serum albumin with known mutations. Mol. Pharmacol. 37: 238-242, 1990.
225. KRASNY, H. C., AND PETTY, B. G.: Metabolism of desciclovir, a prodrug of acyclovir, in humans after multiple oral dosing. J. Clin. Pharmacol. 27: 74-77, 1987.
226. 1-acid glycoprotein in health and disease. Pharmacol. Res. 40: 1-47, 1988.
227. KRENITSKY, T. A., AND ELION, G. B.: Enzymes as tools and targets in drug research. In Strategy in Drug Research, ed. by J. A. Keverling Buisman, pp. 65-87, Elsevier, Amsterdam, 1982.
228. KRENITSKY, T. A., HALL, W. W., DE MIRANDA, P., BEAUCHAMP, L. M., SCHAEFFER. M. J., AND WHITEMAN, P. D.: 6-Deoxyacyclovir: a xanthine oxidase-activated prodrug of acyclovir. Proc. Natl. Acad. Sci. USA 81: 3209-3213, 1984.
229. KROPP, H., SUNDELOF, J. G., KAHAN, J. S., KAHAN, F. M., AND BIRNBAUM, J.: MK-0787 (N-formimidoyl thienamycin): evaluation of in vitro and in vivo activities. Antimicrob. Agents Chemother. 17: 993-1000, 1980.
230. KUNZE, K. L., WIENKERS, L. C., THUMMEL, K. E., AND TRAGER, W. F.: Warfarin-fluconazole: I - inhibition of the human cytochrome P-450-dependent metabolism of warfarin by fluconazole: in vitro studies. Drug Metab. Dispos. 24: 414-421, 1996.
231. KUPFER, A., AND PREISIG, R.: Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26: 753-759, 1984.
232. KURZ, H.: Methodological problems in drug-binding studies. In Drug-protein Binding, ed. by M. M. Reidenberg and S. Erill, pp. 70-92, Fraeger Publishers, New York, 1986.
233. KURZ, H., TRUNK, H., AND WEITZ, B.: Evaluation of methods to determine protein-binding of drugs: equilibrium dialysis, ultrafiltration, ultracentrifugation and gel filtration. Arzneim-Forsch./Drug Res. 27: 1373-1380, 1977.
234. LA DU, B. N.: Human serum paraoxonase/arylesterase. In Pharmacogenetics and Drug Metabolism, ed. by W. Kalow, pp. 51-91, Pergamon Press, New York, 1992.
235. LAURSEN, L. C., BORGA, O., KROHN, L., AND WEEKE, B.: Distribution of enprofylline and theophylline between plasma and cerebrospinal fluid. Ther. Drug Monit. 11: 162-164, 1989.
236. LAWSON, D. H., HENRY, D. A., LOWE, J., REAVEY, P., RENNIE, J. A. N., AND SOLOMAN, A.: Acetylator phenotype in spontaneous SLE and rheumatoid arthritis. Ann. Rheum. Dis. 38: 171-173, 1979.
237. LEAHY, D. E., LYNCH, J., AND TAYLOR, D. D.: Mechanisms of absorption of small molecules. In Novel Drug Delivery, ed. by L. F. Prescott and W. S. Nimmo, pp. 33-44, John Wiley & Sons, New York, 1989.
238. LE BIGOT, J. F., BEGUE, J. M., KIECHEL, J. R., AND GUILLOUZO, A.: Species differences in metabolism of ketotifen in rat, rabbit and human: demonstration of similar pathways in vivo and in cultured hepatocytes. Life Sci. 40: 883-890, 1987.
239. LEE, E. J. D., AND WILLIAMS, K. M.: Chirality: clinical pharmacokinetic and pharmacodynamic considerations. Clin. Pharmacokinet. 18: 339-345, 1990.
240. LEE, E. J. D., WILLIAMS, K. M., DAY, R. O., GRAHAM, G. G., AND CHAMPION, G. D.: Stereoselective disposition of ibuprofen enantiomers in man. Br. J. Clin. Pharmacol. 19: 669-674, 1985.
241. LEGRAVEREND, C., MODE, A., WELLS, T., ROBINSON, I., AND GUSTAFSSON, J-A.: Hepatic steroid hydroxylating enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats. FASEB J. 6: 711-718, 1992a.
242. LEGRAVEREND, C., MODE, A., WESTIN, S., STRÖM, A., EGUCHI, H., ZAPHIROPOULOS, P., AND GUSTAFSSON, J-A.: Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion. Mol. Endocrin. 6: 259-266, 1992b.
243. LEMOINE, A., GAUTIER, J. C., AZOULAY, D., KIFFEL, L, BELLOC, C., GUENGERICH, F. P., MAUREL, P., BEAUNE, P., AND LEREUX, J. P.: Major pathway of imipramine metabolism is catalyzed by cytochrome P-450 1A2 and P-450 3A4 in human liver microsomes. Mol. Parmacol. 43: 827-832, 1993.
244. LENNARD, L., VAN LOON, J., LILLEYMAN, J. S., AND WEINSHILBOUM, R. M.: Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin. Pharmacol. Ther. 41: 18-25, 1987.
245. LENNARD, L., VAN LOON, J., AND WEINSHILBOUM, R. M.: Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin. Pharmacol. Ther 46: 149-154, 1989.
246. LENNERNÄS, H., PALM, K., FAGERHOLM, U., AND ARTURSSON, P.: Correlation between paracellular and transcellular drug permeability in the human jejunum and Caco-2 monolayers. Int. J. Pharm., 127: 103-107, 1996.
247. LEVINE, W. G.: Heavy-metal antagonists. In The Pharmacological Basis of Therapeutics, ed. by L. S. Goodman and A. Gilman, pp. 912-923, Macmillan Publishing Co., Inc., New York, 1975.
248. LEVY, G.: Effect of plasma protein binding of drugs on duration and intensity of pharmacological activity. J. Pharm. Sci. 65: 1264-1265, 1976.
249. LEWIS, R. J., TRAGER, W. F., CHAN, K. K., BRECKENRIDGE, A., ORME, M., ROWLAND, M., AND SCHARY, W.: Warfarin: stereochemical aspects of its metabolism and its interactions with phenylbutazone. J. Clin. Invest. 53: 1607-1617, 1974.
250. LIN, H. J., HAN, C-Y., LIN, B. K., AND HARDY, S.: Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics and whites: application to metabolic epidemiology. Am. J. Hum. Genet. 52: 827-834, 1993a.
251. 2-receptor antagonists: relationship between intrinsic potency and effective plasma concentrations. Clin. Pharmacokinet. 20: 218-236, 1991.
252. LIN, J. H.: Species similarities and differences in pharmacokinetics. Drug Metab. Dispos. 23: 1008-1021, 1995.
253. LIN, J. H.: Bisphosphonates: a review of their pharmacokinetic properties. Bone 18: 75-85, 1996a.
254. LIN, J. H.: In vitro and in vivo drug interaction with indinavir. In Symposium on Recent Advances in Drug-Drug Interactions, Washington, DC, December 10-11, 1996b.
255. LIN, J. H., CHEN, I-W., AND DELUNA, F. A.: Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in experimental polycythemic and anemic rats. Pharm. Res. 8: 608-614, 1991a.
256. LIN, J. H., CHEN, I-W., AND DELUNA, F. A.: Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats. Drug Metab. Dispos. 20: 473-478, 1992.
257. LIN, J. H., CHEN, I-W., AND DELUNA, F. A.: Uptake of alendronate by the bone tissues in hypocalcemic and hypercalcemic rats. Drug Metab. Dispos. 21: 800-804, 1993b.
258. LIN, J. H., CHEN, I-W., AND LIN, T-H.: Species-dependent stereopharmacokinetics of MK-927, a potent carbonic anhydrase inhibitor. Drug Metab. Dispos. 19: 816-822, 1991b.
259. LIN, J. H., CHEN, I-W., AND LIN, T-H.: Blood-brain barrier permeability and in vivo activity of partial agonists of benzodiazepine receptor: a study of L-663,581 and its metabolites in rats. J. Pharmacol. Exp. Ther. 271: 1197-1202, 1994.
260. LIN, J. H., CHEN, I-W., ULM, E. H.. AND DUGGAN, D. E.: Differential effects of phenobarbital on ester and ether glucuronidation of diflunisal in rats. J. Pharmacol. Exp. Ther. 242: 1013-1018, 1987a.
261. LIN, J. H., CHEN, I-W., ULM, E. H., AND DUGGAN, D. E.: Differential renal handling of angiotensin converting enzyme inhibitors enalaprilat and lisinopril in rats. Drug Metab. Dispos. 16: 392-396, 1988.
262. LIN, J. H., CHEN, I-W., ULM, E. H., GEHRET, J. R., AND DUGGAN, D. E.: Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in rabbits following single and multiple doses. Drug Metab. Dispos. 18: 836-841, 1990a.
263. LIN, J. H., CHIBA, M., BALANI, S. K., CHEN, I-W., KWEI, G. Y-S., VASTAG, K. J., AND NISHIME. J. A.: Species differences in the pharmacokinetics and metabolism of indinavir, a potent HIV protease inhibitor. Drug Metab. Dispos. 24: 1111-1120, 1996a.
264. LIN, J. H., CHIBA, M., CHEN, I-W., NISHIME, J. A., AND VASTAG, K. J.: Sex-dependent pharmacokinetics of indinavir: in vivo and in vitro evidence. Drug Metab. Dispos. 24: 1298-1306, 1996b.
265. LIN, J. H., CHIBA, M., CHEN, I-W., VASTAG, K. J., NISHIME, J. A., DORSEY, B. D., MICHAELSON, S., AND MCDANIEL, S. L.: Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys. J. Pharmacol. Exp. Ther. 274: 264-269, 1995.
266. LIN, J. H., COCCHETTO, D. M., AND DUGGAN, D. E.: Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drugs. Clin. Pharmacokinet. 12: 402-432, 1987b.
267. LIN, J. H., DELUNA, F. A., ULM, E. H., AND TOCCO, D. J.: Species-dependent enantioselective plasma protein binding of MK-571, a potent leukotriene D4 antagonist. Drug Metab. Dispos. 18: 464-487, 1990b.
268. LIN, J. H., DUGGAN, D. E., CHEN, I-W., AND ELISWORTH, R. L.: Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab. Dispos. 19: 926-932, 1991c.
269. LIN, J. H., HAYASHI, M., AWAZU, S., AND HANANO, M.: Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat, J. Pharmacokinet. Biopharm. 6: 327-337, 1978.
270. LIN, J. H., AND LEVY, G.: Effect of prevention of inorganic sulfate depletion on the pharmacokinetics of acetaminophen in rats. J. Pharmacol. Exp. Ther. 238: 94-98, 1986.
271. LIN, T. H., AND LIN, J. H.: Effects of protein binding and experimental disease states on brain uptake of benzodiazepines in rats. J. Pharmacol. Exp. Ther. 253: 45-50, 1990.
272. LIN, J. H., STOREY, D. E., CHEN, I-W., AND XU, X.: Improved oral absorption of L-365,260, a poorly soluble drug. Biopharm. Drug Dispos. 17: 1-16, 1996c.
273. LIN, J. H., SUGIYAMA, Y., AWAZU, S., AND HANANO, M.: In vitro and in vivo evaluation of tissue to plasma partition coefficient for physiological pharmacokinetic model, J. Pharmacokinet. Biopharm. 10: 637-647, 1962.
274. LIN, J. H., ULM, E. H., AND LOS, L. E.: Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H-4(isobutylamino)thieno(2, 3, Bithiopyran-2-sulfonamide-7,7-dioxide (MK-927), a potent carbonic anhydrase inhibitor, in rats. Drug Metab. Dispos. 19: 233-238, 1991d.
275. LINDBERG, L. P., AND NEGISHI, M.: Alternation of mouse cytochrome P450coh substrate specificity by mutation of a single amino-acid residue. Nature (Lond.) 339: 632-634, 1989.
276. LINTON, A. L., LUKE, R. G., AND BRIGGS, M. D.: Methods of forced diuresis and its application in barbiturate poisoning. Lancet ii: 377-380, 1967.
277. LLERENA, A. L., ALM, C., DAHL, M-J., EKQUIST, B., AND BERTILSSON, L.: Halo-peridol disposition is dependent on debrisoquine oxidation phenotype. Ther. Drug Munit. 14: 92-97, 1992.
278. LOCKRIDGE, O.: Genetic variants of human serum buthrylcholinesterase influence the metabolism of muscle relaxant succinylcholine. In Pharmacogenetics of Drug Metabolism, ed. by W. Kalow, pp. 15-50, Pergamon Press, New York, 1992.
279. LOO, J. C. K., FOLTZ, E. L., WALLICK, H., AND KWAS, K. C.: Pharmacokinetics of pivampicillin and ampicillin in man. Clin. Pharmacol. Ther. 16: 35-43, 1974,
280. 1-acid glycoprotein: effect on drug binding. In Drug-Protein Binding, ed. by M. M. Reidenberg and S. Erill, pp. 201-219, Praeger, New York, 1986.
281. MACKICHAN, J. J.: Pharmacokinetic consequences of drug displacement from blood and tissue proteins. Clin. Pharmacokinet. 9: 32-41, 1984.
282. MACKICHAN, J. J.: Protein binding drug displacement interactions: fact or fiction. Clin. Pharmacokinet. 16: 65-73, 1989.
283. MACLEOD, J. N., SORENSEN, M. P., AND SHAPIRO, B. H.: Strain independent elevation of hepatic monooxygenase enzyme in female mice. Xenobiotics 17: 1095-1102, 1987.
284. MACPHERSON, C. R., MILINE, M. D., AND EVANS, D. M.: The excretion of salicylate. Br. J. Pharmacol. 10: 484-489, 1955.
285. MAHGOUB, A., IDLE, J. R., DRING, L. G., LANCASTER, R., AND SMITH, R. L.: Polymorphic hydroxylation of debrisoquine in man. Lancet ii: 584-586, 1977.
286. MANZEL-SOGLOWEK, S., GEISSLINGER, G., BECK, W. S., AND BRUNE, K.: Variability of inversion of (R)-flurbiprofen in different species. J. Pharm. Sci. 81: 888-891, 1992.
287. MARSDEN, C. D.: Advances in the management of Parkinson's disease. Scott. Med. J. 21: 139-148, 1976.
288. MARTIN, Y. C., AND HANSCH, C.: Influence of hydrophobic character on the relative rate of oxidation of drugs by rat liver microsomes. J. Med. Chem. 14: 777-779, 1971.
289. MAY, F. E., STEWART, R. B., AND CLUFF, L. E.: Drug interactions and multiple drug administration. Clin. Pharmacol. Ther. 22: 323-327, 1977.
290. MCCREA, J., WOOLK, E., STERRETT, A., MATTHEWS, C., DEUTSCH, P., YEH, K. C., WALDMAN, S., AND BJORNSSON, T.: Effects of ketoconazole and other P-450 inhibitors on the pharmacokinetics of indinavir. (Abstract) Pharm. Res. 13(suppl.):S485, 1996.
291. MCDONNELI, W. M., SCHEIMAN, J. M., AND TRABER, P. G.: Induction of cytochrome P450 IA genes (CYP 1A) by omepraxole in the human alimentary tract. Gastroenterology 103: 1509-1516, 1992.
292. MEYER, H., AND MALLY, J.: über hydrazinderivate der pyridin-carbonsussen. Mk. Chem. 33: 393-414, 1912.
293. MEYER, J. H.: Motility of stomach and gastroduodenal junction. In Physiology of the Gastrointestinal Tract, ed. by L. R. Johnson, pp. 613-629, Raven Press, New York, 1987.
294. MEYER, J. W., WOGOON, B., BALMANN, P., AND MEYER, U. A.: Slow sulphoxidation of thioridazine in a poor metabolizer of debrisoquine type. Eur. J. Clin. Pharmacol. 39: 613-614, 1990a.
295. MEYER, U. A.: The molecular basis of genetic polymorphisms of drug metabolism. J. Pharm. Pharmacol. 46(suppl. 1): 409-415, 1994.
296. MEYER, U. A., BLUM, M., GRANT, D. M., HEIM, M., BROLY, F., HOFFMANN, F., PROBST, M., AND GARCIA-AGUNDEZ, J.: Acetylation pharmacogenetics. In Human Drug Metabolism: From Molecular Biology to Man, ed. by E. H. Jefferey, pp. 117-124, CRC Press, Boca Raton, FL, 1993.
297. MEYER, U. A., SKODA, R. C., ZANGER, U. M., HEIM, M., AND BROLY, K.: The genetic polymorphism of debrisoquine/sparteine metabolism: molecular mechanisms. In Pharmacogenetics of Drug Metabolism, ed. by W. Kallow, pp. 609-623, Pergamon Press, New York, 1992.
298. MEYER, U. A., ZANGER, U. M., GRANT, D., AND BLUM, M.: Genetic polymorphisms of drug metabolism. Adv. Drug Res. 19: 197-241, 1990b.
299. MILLER, J. A., AND SURH, Y-J.: Sulfonation in chemical carcinogenesis. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 429-457, Springer-Verlag, Berlin, Germany, 1994.
300. MILOVICI, V., OLSSON, S., OCKLIND, G., HOCHMAN, J., PAUL, E. C. A., AND ARTURSSON, P.: A new intestinal epithelial cell culture model (2/4/A1) for studies of paracellular drug transport. (Abstract) Pharm. Res. 13(suppl.): 358S, 1996.
301. MINERS, J. O., LILLYWHITE, K. J., AND BIRKETT, D. J.: In vitro evidence for the involvement of at least two forms of human liver UDP-glucuronosyltransferase in morphine 3-glucuronidation. Biochem. Pharmacol. 37: 2839-2845, 1988.
302. MITCHELL, J. R., ZlMMERMAN, H. J., ISHAK, K. G., THORGEIRSSON, U. P., TIMBRELL, J. A., SNODGRASS, W. R., AND NELSON, S. D.: Isoniazid liver injury: clinical spectrum, pathology and possible pathogenesis. Ann. Intern. Med. 84: 181-192, 1976.
303. MOMMSEN, S., AND AAGAARD, J.: Tobacco as a risk factor in bladder cancer. Carcinogenesis 4: 335-338, 1983.
304. MONAHAN, B. P., FERGUSON, C. L., KILLEAVY, E. S., LLOYD, B. K., TROY, J., AND CANTILENA, L. R.: Torsades de points occurring in association with terfena- dine use. JAMA 264: 2788-2790, 1990.
305. MONKS, T. J., AND LAU, S. S.: Toxicology of quinone-thinethers. CRC Crit. Rev. Toxicol. 22: 243-270, 1992.
306. MONKS, T. J., AND LAU, S. S.: Glutathione conjugation as a mechanism for the transport of reactive metabolites. Adv. Pharmacol. 27: 183-210, 1994.
307. MONKS, T. J., AND LAU, S. S.: Glutathione conjugate-mediated toxicities. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 459-509, Springer-Verlag, Berlin, Germany, 1994.
308. MORDENTI, J.: Pharmacokinetic scale-up: accurate prediction of human phar- macokinetic profiles from animal data. J. Pharm. Sci. 74: 1097-1099, 1985.
309. MULDER, G. J.: Pharmacological effects of drug conjugates: is morphine 6-glu- curonide an exception? Trends Pharmacol. Sci. 13: 302-304, 1992.
310. MULDER, G. J., GROEN, K., TIJDENS, R. B., AND MEIJER, D. K. F.: Pharmacoki- netics of Xamoterol glucuronidation in the rat in vivo and in liver perfusion. Xenobiotica 17: 85-92, 1987.
311. MUNGALL, D., LUDDEN, T. M., MARSHALL, J., AND HAWKINS, D.: Relationships between steady-state warfarin concentrations and anticoagulant effect. Clin. Pharmacokinet. 9(suppl. 1): 99-100, 1984.
312. MURRAY, M,: Mechanisms of the inhibition of cytochrome P-460-mediated drug oxidation by therapeutic agents. Drug Metab. Rev. 18: 55-81, 1987.
313. MUTSCHLER, E., AND DKRKNDORK, H.: Muscle relaxants. In Drug Actions: Basic Principles and Therapeutic Aspects, ed. by E. Mutschler and H. Derendorf, pp. 195-203, CRC Press, Boca Raton, FL, 1995.
314. MUTSCHLER, E., AND DERENDORF, H.: Ulcer therapy. In Drug Actions: Basic Principles and Therapeutic Aspects, ed. by E. Mutschler and H. Derendorf, pp. 424-429, CRC Press, Boca Raton, FL, 1995.
315. NEBERT, D. W., AND GONZALEZ, K. J.: The P450 gene superfamily. In Principles, Mechanisms and Biological Consequences of Induction, ed. by K. Ruckpaul and H. Rein, pp. 35-61, Taylor & Francis, London, UK, 1990.
316. NELSON, D. R., KAMATAKI, T., WAXMAN, D. J., GUENGERICH, F. P., ESTABROOK, R. W., FEYEREISEN, H., GONZALEZ, F. J., COON, M. J., GUNSALUS, I. C., GOTOH, O., OKUDA, K., AND NEBERT, D. W.: The P-450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12: 1-51, 1993.
317. NELSON, D. R., KOYMANS, L., KAMATAKI, T., STEGEMAN, J. J., FEYEREISEN, R., WAXMAN, D. J., WATERMAN, M. R., GOTOH, O., COON, M. J., ESTABROOK, R. W., GUNSALUS, I. C., AND NEHERT, D. W.: P450 superfamily, update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 8: 1-42, 1996.
318. NEWTON, D. J., WANG, R. W., AND LU, A. Y. H.: Cytochrome P-450 inhibitors: evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab. Dispos. 23: 154-158, 1995.
319. NIMMO, W. S.: Drugs, disease and gastric emptying. Clin. Pharmacokinet. 1: 189-203, 1976.
320. NIOPAS, I., TOON, S., AND ROWLAND, M.: Further insight into the stereo-selective interaction between warfarin and cimetidine in man. Br. J. Clin. Pharmacol. 32: 508-511, 1991.
321. OCHS, H. R., GREENBLATT, D. J., ABERDNETHY, D. R., ARENDT, R. M., GERLOFF, J., EICHELKRAUT, W., AND HAHN, N.: Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility. J. Pharm. Pharmacol. 37: 428-431, 1985.
322. ØIE, S., AND CHIANG, J.: Drug binding and pharmacologic activity of x,-adrenergic antagonisis. In Plasma binding nf drugs and its consequences, ed. by P Belpaire, M. Bogaert, J. P. Tillement, and R. Verbeeck, pp. 159-169, Academia Press, Ghent, Belgium, 1991.
323. ØIE, S., AND LEVY, G.: Effect of salicylic acid on pharmacokinetics of free and plasma protein bound bilirubin in experimental unconjugated hyperbilirubinemia. J. Pharm. Sci. 68: 1-6, 1979a.
324. ØIE, S., AND LEVY, G.: Effect of sulfisoxazole on pharmacokinetics of free and plasma protein bound bilirubin in experimental unconjugated hyperbilirubinemia. J. Pharm. Sci. 68: 6-8, 1979b.
325. ONDETTI, M. A.: Structural relationships of angiotensin-converting enzyme inhibitors to pharmacologic activity. Circulation 77(suppl.): 174-178, 1988.
326. O'REILLY, R. A., TRAGER, W. F., MOTLEY, C. H., AND HOWALD, W. M.: Stereoselective interaction of phenylbutazone with [12C/13C] warfarin pseudoracemates in man. J. Clin. Invest. 65: 746-753, 1980.
327. OSBORNE, R., THOMPSON, P., JOEL, S., TREW, D., PATEL, N., AND SLEVIN, M.: The analgesic activity of morphine 6-glucuronide. Br. J. Clin. Pharmacol. 34: 130-138, 1992.
328. OSIECKA, I., PORTER, P. A., BOHCHARDT, R. T., FIX, J. A., AND GARDNER, C. R.: In vitro drug absorption models: I - brush border membrane vesicles, isolated mucosal cells and everted intestinal rings: characterization and salicylate accumulation. Pharm. Res. 2: 284-292, 1985.
329. PADGHAM, C. R. W., AND PAINE, A. J.: Altered expression of cytochrome P-450 mRN'A's, and potentially of other transcripts encoding key hepatic functions. are triggered during the isolation of rat hepatocytes. Biochem. J. 289: 621-624, 1993.
330. PADGHAM, C. R. W., PAINE, A. J., PHILLIPS, I. R., AND SHEPPARD, E. A.: Maintenance of total cytochrome P-450 content in rat hepatocyte culture and the abundance of CYP1A2 and CYP2B1/2 in RNAs. Biochem. J. 285: 929-932, 1992.
331. PANG, K. S., AND CHIBA, M.: Metabolism: scaling-up from in vitro to organ and whole body. In Handbook of Experimental Pharmacology: Pharmacokinetics of Drugs, ed. by P. G. Welling and L. P. Balant, vol. 110, pp. 101-187, Springer-Verlag, Berlin, Germany, 1994.
332. PANTUCK, E. J.: Stimulatory effect of brussel sprouts and cabbage in human drug metabolism. Clin. Pharmacol. Ther. 25: 88-92, 1979.
333. PAPPENHEIMER, J. R.: Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 100: 123-136, 1987.
334. PARDRIDGE, W. M.: Transport of protein-bound hormones into tissues in vivo. Endocr. Rev. 2: 103-123, 1980.
335. PARDRIDGE, W. M.: Development of brain-specific transport vectors: a molecular biological response. In Peptide Drug Delivery to the Brain, ed. by W. M. Pardridge, pp. 280-302, Raven Press, New York, 1991.
336. PARK, B. K., AND KITTERINGHAM, N. R.: Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab. Rev. 26: 625-643, 1994.
337. PARK B. K., AND KITTERINGHAM, N. R.: Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications. Xenobiotics 20: 1171-1185, 1990.
338. PARKINSON, A.: An overview of current cytochrome P-450 technology for assessing the safety and efficacy of new materials. Toxicol. Pathol. 24: 45-57, 1996.
339. PATCHETT, A. A., HARIS, E., TRISTRAM, E. W., WYVRATT, M. J., WU, M. T., TAUB, D., PETERSON, E. R., IKELER, T. J., TEN BROEKE, J., PAYNE, L. G., ONDEYKA, D. L., THORSETT, E. D., GRENLEE, W. J., LOHR, N. S., HOTTSOMMER, R. D., JOSHUA, H., RUYLE, W. V., ROTHROCK, J. W., ASTER, S. D., MAYCOCK, A. L., ROBINSON, F. M., HIRSCHMANN, R., SWEET, C. S., ULM, E. H., GROSS, D. M., VASSIL, T. C., AND STONE, C. A.: A new class of angiotensin-converting enzyme inhibitors. Nature (Lond.) 288: 280-283, 1980.
340. PAUL, D., STANDIFER, K. M., INTURRISI, C. E., AND PASTERNAK, G. W.: Pharmacological characterization of morphine 6-glucuronide, a very potent morphine metabolite. J. Pharmacol. Exp. Ther. 251: 477-483, 1989.
341. PECK, C. C., TEMPLE, R., AND COLLINS, J. M.: Understanding consequences of concurrent therapies. JAMA 269: 1550-1552, 1993.
342. PFEIFFER, N.: The potential for topical carbonic anhydrase inhibitors in glaucoma therapy. Curr. Opinion in Ophthalmology 5: 20-25, 1994.
343. 1-acid glycoprotein for interindividual variation. Clin. Pharmacol. Ther. 22: 545-549, 1977.
344. 1-acid glycoprotein. N. Engl. J. Med. 299: 1435-1439, 1978.
345. POWIS, G.: The use of human liver for foreign compound metabolism and toxicity studies. Drug Metab. Rev. 20: 379-394, 1989.
346. POWIS, G., MELDER, D. C., AND WILKE, T. J.: Human and dog, but not rat, isolated hepatocytes have decreased foreign compound-metabolizing activities compared to liver slices. Drug Metab. Dispos. 17: 526-531, 1989.
347. PRENTIS, R. A., LIS, Y., AND WALKER, S. R.: Pharmaceutical innovation by seven UK-owned pharmaceutical companies (1964-1985). Br. J. Clin. Pharmacol. 25: 387-396, 1988.
348. PRICE, R. A., KEITH, R. A., SPIELMAN, R. S., AND WEINSHILBOUM, H. M.: Major gene polymorphism for human erythrocyte (RBC) thio methyltransferase (TMT). Genet. Epidemiol. 6: 651-662, 1989.
349. QUELLEC, A. L., DUPIN, S., TUFENKJI, A. E., GENISSEL, P., AND HOUIN, G.: Microdialysis: an alternative for in vitro and in vivo protein binding studies. Pharm. Res. 11: 835-838, 1994.
350. RANEY, K. D., COLES, B. F., GUENGERICH, F. P., AND HARRIS, T. M.: The endo-8,9-epoxide of alfatoxin B1: a new metabolite. Chem. Res. Toxicol. 5: 333-335, 1992.
351. RAPOPORT, S. I.: Transport in cells and tissues. In Blood-Brain Barrier in Physiology and Medicine, ed. by S. I. Rapoport, pp. 153-176, Haven Press, New York, 1976.
352. REES, P. J., SELBY, P., PRENTICE, H. G., WHITEMAN, P. D., AND GRANT, D. M.: A prodrug of acyclovir with increased bioavailability. J. Antimicrob. Chemother. 18(suppl. B): 215-222, 1986.
353. REGÅRDH, C. G., GABRIELSSON, M., HOFFMAN, K. J., LÖFBERG, I., AND SKÅNBERG, I.: Phurmacokinetics and metabolism of omeprazole in animals and man: an overview. Scand. J. Gastroenterol. 20(suppl. 108): 79-94, 1985.
354. REINDENBERG, M. M., AND MARTIN, J. H.: The acctylator phenotype of patients with systemic lupus erythematosus. Drug Metab. Dispos. 3: 71-73, 1974.
355. REITZ, R. H., MANDRALA, A. L., AND GUENGERICH, F. P.: In vitro metabolism of methylene chloride in humans and animal tissues: use in physiologically based pharmacokinetic models. Toxicol. Appl. Pharmacol. 97: 230-246, 1989.
356. REITZ, R. H., MANDRALA, A. L,., PARK, C. N., ANDERSON, M. E., AND GUENGERICH, F. P.: Incorporation of in vitro enzyme data into the physiologically based pharmacokinetic model for methylene chloride: implications for risk assessment. Toxicol. Lett. 43: 97-116, 1988.
357. REMMEL, R. P., AND BURCHELI., B.: Validation and use of cloned, expressed human drug-metabolizing enzymes in heterologous cells for analysis of drug metabolism and drug-drug interactions. Biochem. Pharmacol, 46: 559-566, 1993.
358. REMMER, H.: Die Beschleunigung des Evipanabbaues unter der Wirkung Von Barbituraten. Naturwissenschaften 8: 189-191, 1958.
359. RESETAR, A., AND SPECTOR, T.: Glucuronidation of 3′-azido-3′-deoxythymidine: human and rat enzyme specificity. Biochem. Pharmacol. 38: 1389-1393, 1989.
360. RICE, J. M., DIWAN, B. A., WARD, J. M., NIMES, R. W., AND LUBET, R. A.: Phenobarbital and related compounds: approaches to interspecies extrapolation. Prog. Clin. Biol. Res. 374: 231-249, 1992.
361. RICHARDSON, K.: The discovery of fluconazole. DN&P 6: 299-303, 1993.
362. RIESENMAN, C.: Antidepressant drug interactions and the cytochrome P-450 system: a critical appraisal. Pharmacotherapy 15: 84S-99S, 1995.
363. RIMMER, E. M., BUSS, D. C., ROUTLEDGE, P. A., AND RICHENS, A.: Should we routinely measure free plasma phenytoin concentration? Br. J. Clin. Pharmacol. 17: 99-102, 1984.
364. ROBITZEK, E. H., SELIKOFF, I. J., AND ORNSTEIN, G. G.: Chemotherapy of human tuberculosis with hydrazine derivatives of isonicotinic acid. Q. Bull. Sea View Hosp. N. Y. 13: 27-31, 1952.
365. RODRIGUES, A. D.: Use of in vitro human metabolism studies in drug development: an industrial perspective. Biochem. Pharmacol. 48: 2147-2156, 1994.
366. ROGERS, S. M., BACK, D. J., AND ORME, L. E.: Intestinal metabolism of ethinyloestradiol and paracetamol in vitro: studies using using chambers. Br. J. Clin. Pharmacol. 23: 727-734, 1987.
367. ROWLAND, M.: Plasma protein binding and therapeutic drug monitoring. Ther. Drug Monit. 2: 29-37, 1980.
368. RUBAS, W., JEZYK, N., AND GRASS, G. M.: Comparison of permeability characteristics of a human colonie epithelial (Caco-2) cell lilne to colon of rabbit, monkey, and dog intestine and human drug absorption. Pharm. Res. 10: 113-118, 1993.
369. SATOH, T.: Role of carboxylesterases in xenobiotic metabolism. In Review in Biochemical Toxicology, ed. by E. Hodgson, J. H. Bend, and R. M. Philot, vol. 8, pp. 155-181, Elsevier, Amsterdam, 1987.
370. SAWADA, Y., HANANO, M., SUGIYAMA, Y., HARASHIMA, H., AND IGA, T.: Prediction of the volumes of distribution of basic drugs in humans based on data from animals. J. Pharmacokinet. Biopharm. 12: 587-596, 1964a.
371. SAWADA, Y., HANANO, M., SUGIYAMA, Y., AND IGA, T.: Prediction of the disposition of β-lactam antibiotics from pharmacokinetic parameters in animals, J. Pharmacokinet. Biopharm. 12: 241-261, 1984b.
372. SCHANKER, L. S.: On the mechanism of absorption from the gastrointestinal tract. J. Med. Pharm. Chem. 2: 343-346, 1960.
373. SCHUHMANN, G., FICHTL, B., AND KURZ, H.: Prediction of drug distribution in vivo on the basis of in vitro binding data. Biopharm. Drug Dispos. 8: 73-86, 1987.
374. SCHULTZ, P. A.: The role of genetic factors in bladder cancer. Cancer Detect. Prev. 11: 379-388, 1988.
375. SEGEL, I. H.: Simple inhibition systems: competitive inhibition. In Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems, ed. by I. H. Segel, pp. 100-112, John Wiley & Sons, New York, 1975.
376. SELLERS, E. M.: Plasma protein displacement interactions are rarely of clinical significance. Pharmacology 18: 225-227, 1979.
377. SELLERS, E. M: Drug displacement interactions: a case study of the phenyl-butazone-warfarin interaction. In Drug-Protein Binding, ed. by M. M. Reidenberg and S. Erill, pp. 257-273, Praeger, New York, 1986.
378. SESARDIC, D., BOOBIS, A. R., MURRAY, P., MURRAY, S., SEGURA, J., DELA TORRE, R., AND DAVIES, D. S.: Furafylline is a potent and selective inhibitor of cytochrome P450 IA2 in man. Br. J. Clin. Pharmacol. 29: 651-663, 1990.
379. SEYDEL, J. K., MILLER, G., AND DOUKAS, P. H.: Structure-activity correlations of sulfonamides in cell-free systems compared to correlations obtained in whole cell systems and in vivo. In Medicinal Chemistry, ed. by P. Pratesi, pp. 139-151, Butterworths, London, UK, 1973.
380. SEYDEL, J. K., AND SCHAPER, K. J.: Quantitative structure-pharmacokinetic relationships and drug design. In Pharmacokinetics: Theory and Methodology, ed. by M. Rowland and G. Tucker, pp. 311-366, Pergamon Press, New York, 1986.
381. SHAPIRO, B. H., AGRAWAL, A. K., AND PAMPORI, N. A.: Gender differences in drug metabolism regulated by growth hormone. Int. J. Biochem. Cell Biol. 27: 9-20, 1995.
382. SHARE, N. N., LOTTI, V. J., AND GAUTHERON, P.: R-enantiomer of timolol: a potential selective ocular antihypertensive agent. Graefe's Arch. Clin. Exp. Ophthalmol. 221: 234-238, 1984.
383. SHEN, D. D., LEVY, R. H., SAVITCH, J. L., BODDY, A. V., LEPAGE, F., AND TOMBRET, F.: Comparative anticonvulsant potency and pharmacokinetics of the (+)- and (-)-enantiomers of stiripentol. Epilepsy Res. 12: 29-36, 1992.
384. SHEN, T. Y.: Perspectives in non-steroidal anti-inflammatory agents. Angew. Chem. Int. Ed. Engl. 11: 460-472, 1972.
385. SHEN, T. Y., AND WINTER, C. A.: Chemical and biological studies on indomethacin, sulindac and their analogs. Adv. Drug Res. 12: 90-245, 1977.
386. SHEN, W. W.: Cytochrome P-450 monooxygenase and interactions of psychotropic drugs: a five-year update. Int. J. Psychiatry Med. 26: 277-290, 1995.
387. SHIMADA, T., YAMAZAKI, H., MIMURA, M., INUI, Y., AND GITENGERICH, F. P.: Intel-individual variations in human liver cytochrome P-450 enzymes involved in oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270: 414-422, 1994.
388. SHOU, M., GROGAN, J. O., MANCEWICZ, J. A., KRAUSZ, K. W., GONZALEZ, F. J., GELBOIN, H. V., AND KORZEKWA, K. R.: Activation of CYP3A4: evidence for simultaneous binding of two substrates in a cytochrome P450 active site. Biochemistry 33: 6450-6455, 1994.
389. SIDDOWAY, L. A., THOMPSON, K. A., MCALLISTER, C. B., WANG, T., WILKINSON, G. R., RODEN, D. M., AND WOOSLEY, R. L.: Polymorphism of prnpafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785-791, 1987.
390. SILBER, B., HOLFORD, N. H. G., AND RIEGELMAN, S.: Stereoselective disposition and glucuronidation of propranolol in humans. J. Pharm. Sci. 71: 699-704, 1982.
391. SILBERSTEIN, D. J., BOWMER, C. J., AND YATES, M. S.: Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure. Br. J. Pharmacol. 95: 343-352, 1988.
392. SIMONYI, M.: On chiral drug action. Med. Res. Rev. 4: 359-413, 1984.
393. SINDRUP, S. H., BRØSEN, K., BJERRING, P., AKENDT-NIELSEN, L., LARSEN, U., ANGELO, H. R., AND GRAM, L. F.: Codeine increases pain thresholds to copper vapor stimuli in extensive but no poor metabolizers of Sparteine. Clin. Pharmacol. Ther. 49: 686-693, 1991.
394. SISENWINE, S. F., TIO, C. O., HADLEY, K. V., LIU, A. L., KIMMEL, H. B., AND RUELIUS, H. W.: Species-related differences in the Stereoselective glucuronidation of oxazepam. Drug Metab. Dispos. 10: 605-608, 1982.
395. SJÖQVIST, F., AND KOIKE, Y.: Intel-individual differences in drug-protein binding. In Drug-Protein Binding, ed. by M. M. Reidenberg and S. Erill, pp. 141-152, Praeger, New York, 1986.
396. SKETT, P.: Biochemical basis of sex differences in drug metabolism. Pharmacol. Ther. 38: 269-304, 1989,
397. SLATTERY, J. T., AND LEVY, G.: Acetaminophen kinetics in acutely poisoned patients. Clin. Pharmacol. Ther. 25: 185-195, 1979.
398. SMITH, D. A.: Species differences in metabolism and pharmacokinetics: are we close to an understanding? Drug Metab. Rev. 23: 355-373, 1993.
399. SMITH, R. L.: Excretion of drugs in bile. In Handbook of Experimental Pharmacology: Concepts in Biochemical Pharmacology, ed. by B. B. Brodie and J. R. Gillette, pp. 354-389, vol. 28, Springer-Verlag, Berlin, Germany, 1971.
400. SOMOGYI, A., AND GUGLER, R.: Drug interactions with cimetidine. Clin. Pharmacokinet. 7: 23-41, 1982.
401. SOONS, P. A., SCHELLENS, J. H. M., AND BREIMER, D. D.: Variability in pharmacokinetics and metabolism of nifedipine and other dihydropyridine calcium entry blockers. In Pharmacogenetics of Drug Metabolism, ed. by E. Kalow, pp. 769-790, Pergamon Press, New York, 1992.
402. SRINIVAS, N. R., HUBBARD, J. W., MCKAY, C., HAWES, E. M., AND MIDHA, K. K.: In vitro hydrolysis of RR, SS-threo-methylphenidate by blood esterases: differential and enantioselective interspecies variability. Chirality 3: 99-103, 1991.
403. STEARNS, R. A., CHAKRAVARTY, P. K., CHEN, R., AND CHIU, S. H. L.: Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes: role of cytochrome P-4502C and 3A subfamily members. Drug Metab. Dispos. 23: 207-215, 1996.
404. STEARNS, R. A., MILLER, R. R., Doss, G. A., CHAKRAVARTY, P. K., ROSEOGAY, A., GATTO, G. J., AND CHIU, S-H. L.: The metabolism of Dup 753, a nonpeptide angiotensin II receptor antagonist by rat, monkey and human liver slices. Drug Metab. Dispos. 20: 281-287, 1992.
405. STEIN, W. D.: The molecular basis of diffusion across cell membranes. In The Movement of Molecules Across Cell Membrane, ed. by W. D. Stein, pp. 65-125, Academic Press, New York, 1967.
406. STELLA, V. J.: Prodrugs and site-specific drug delivery. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 109-116, Taylor & Francis, New York, 1989.
407. STELLA, V. J., AND HIMMELSTEIN, K. J.: Prodrugs and site-specific drug delivery. J. Med. Chem. 23: 1275-1282, 1980.
408. STEVENS, J. C., SHIPLEY, L. A., CASHMAN, J. R., VANDENBHANDEN, M., AND WRIGHTON, S. A.: Comparison of human and Rhesus monkey in vitro phase I and phase II hepatic drug metabolism activities. Drug Metab. Dispos. 21: 753-760, 1993.
409. STEVENSON, C. L., AUGUSTLINS, P. F., AND HENDREN, R. W.: Permeability screen for synthetic peptide combinatorial libraries using Caco-2 cell monolayers and LC/MS/MS. Pharm. Res. 12: 3-94, 1995.
410. STEWART, B. H., CHAN, O. H., Lu, R. H., REYNER, E. L., SCHMID, H. L., HAMILTON, H. W., STEINHAUGH, B. A., AND TAYLOR, M. D.: Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: relationship to absorption in humans. Pharm. Res. 12: 693-699, 1995.
411. STONARD, M. D., PHILIPS, P. G. N., FOSTER, J. R., SIMPSON, M. G., AND LOCK, E. A.: α2u-Globulin: measurement in rat kidney and relationship to hyaline droplets. Clin. Chim. Acta. 160: 197-203, 1986.
412. STROLIN BENEDETTI, M., AND DOSTERT, P.: Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies. Environ. Health Perspect. 102(suppl. 9): 101-105, 1994.
413. SUDA, H., OKAMOTO, M., AND FUKUMOTO, M.: Delayed-type skin allergic reaction in guinea pigs induced by anti-rheumatic compounds with sulfhydryl groups. Immunopharmacol. Immunotoxicol. 15: 387-396, 1993.
414. SUGIYAMA, Y., SAWADA, Y., IGA, T., AND HANANO, M.: Reconstruction of in vivo metabolism from in vitro data. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 225-235, Taylor & Francis, London, 1989.
415. SWARM, R. L., ROBERTS, G. K. S., LEVY, A. C., AND HINES, L. K.: Observations on the thyroid gland in rats following the administration of sulfamethoxazole and trimethoprim. Toxicol. Appl. Pharmacol. 24: 351-363, 1973.
416. SZUMLANSKI, C. L., SCOTT, M. C., AND WEINSHILBOUM, R. M.: Thiopurine methyltransferase pharmacogenetics: human liver enzyme activity. Clin. Pharmacol. Ther. 43: 134-139, 1988.
417. TANG, C., ZHANG, K., LEPAGE, F., LEVY, R. H., AND BAILLIE, T. A.: Metabolic chiral inversion of stiripentol in the rat: II - influence of route of administration. Drug Metab. Dispos. 22: 554-560, 1994.
418. TAN-LIU, D. D., WILLIAMS, R. L., AND RIEGELMAN, S.: Nonlinear theophylline elimination. Clin. Pharmacol. Ther. 31: 358-369, 1982.
419. TAYLOR, D. C., DOWNALL, R., AND BURKE, W.: The absorption of β-adrenoceptor antagonists in rat in situ small intestine: the effect of lipophilicity. J. Pharm. Pharmacol. 37: 280-283, 1985.
420. TEGNER, K., BORGA, O., AND SVENSSON, J.: Protein binding of enprofylline. Eur. J. Clin. Pharmacol. 25: 703-708, 1983.
421. TESTA, B.: Substrate and product stereoselectivity in monooxygenase-mediated drug activation and inactivation. Biochem. Pharmacol. 37: 85-92, 1988.
422. TESTA, B.: Conceptual and mechanistic overview of stereoselective drug metabolism. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 153-160, Taylor & Francis, London, UK, 1989a.
423. TESTA, B.: Mechanisms of chiral recognition in xenobiotic metabolism and drug-receptor interactions. Chirality 1: 7-9, 1989b.
424. TESTA, B., AND TRAGER, W. F.: Racemates versus enantiomers in drug development: dogmatism or pragmatism? Chirality 2: 129-133, 1990.
425. TEW, K. D., HOUGHTON, P. J., AND HOUGHTON, J. A.: Modulation of p-glyeoprotein-mediated multidrug resistance. In Preclinical and Clinical Modulation of Anticancer Drugs, ed. by K. D. Tew, P. J. Houghton, and J. A. Houghton, pp. 125-196, CRC Press, Boca Raton, FL, 1993.
426. THAKKER, D. R., LEVIN, W., WOOD, A. W., CONNEY, A. H., YAGI, H., AND JERINA, D. M.: Stereoselective biotransformation of polycyclical aromatic hydrocarbons to ultimate carcinogens. In Drug Stereochemistry: Analytical Methods and Pharmacology, ed. by I. W. Wainer and D. E. Drayer, pp. 271-296, Marcel Dekker, Inc., New York, 1988.
427. THORGEIRSSON, S. S., ATLAS, S. A., BOOMS, A. R, AND FELTON, J. S.: Species differences in the substrate specificity of hepatic cytochrorm; P-448 from plycyclic hydrocarbon-treated animals. Biochem. Pharmacol. 28: 217-226, 1979.
428. TOBERT, J. A., CHIRILLO, V. J., AND HITZENBERGER, G.: Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomers in man. Clin. Pharmacol. Ther. 29: 344-350, 1981.
429. TOCCO, D. J., DELUNA, F. A., DUNCAN, A. E. W., HSIEH, J. H., AND LIN, J. H.: Interspecies differences in stereoselective protein binding and clearance of MK-571. Drug Metab. Dispos. 18: 388-392, 1990.
430. TOCCO, D. J., DELUNA, F. A., DUNCAN, A. E. W., VASSIL, T. C., AND ULM, E. H.: The physiological disposition and metabolism of enalapril maleate in laboratory animals. Drug Metab. Dispos. 10: 15-19, 1982.
431. TOON, S., HOPKINS, K. J., GARSTANG, F. M., AARONS, L., SEDMAN, A., AND ROWLAND, M.: Enoxacin-warfarin interaction: pharmacokinetics and stereochemical aspects. Clin. Pharmacol. Ther. 44: 32-41, 1987.
432. TOON, S., AND ROWLAND, M.: Structure-pharmacokinetic relationships among the barbiturates in the rat. J. Pharmacol. Exp. Ther. 225: 752-763, 1983.
433. TRAGER, W. F.: Stereochemistry of P-450 catalyzed reactions. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 171-177, Taylor & Francis, London, UK, 1989.
434. TRAGER, W. F., AND TESTA, B.: Stereoselective drug disposition. In Drug Metabolism and Disposition, ed. by G. R. Wilkinson and D. M. Rawlins, pp. 35-61, MTP Press, Lancaster, England, 1985.
435. TUCKER, G. T.: The rational selection of drug interaction studies: implications of recent advances in drug metabolism. Int. J. Clin. Pharmacol. Ther. Toxicol. 30: 550-553, 1992.
436. TURGEON, J., PAVLOU, H. N., WONG, W., FCNCK-BRENTANO, C., AND RODEN, D. M.: Genetically determinated steady-state interaction between encainide and quinidine in patients with arrhythmias. J. Pharmacol. Exp. Ther. 255: 642-649, 1990.
437. TWISS, I. M., DE LA WATER, R., DEN HARTIGH, J., SHARIDANS, R., RAM-KOOP-MANSCHAP, W., BRILL, H., WIJDEVELD, M., AND VERMEIJ, P.: Cytotoxic effects of pamidronate on monolayers of human intestinal epithelial (Cuco-2) cells and its epithelial transport. J. Pharm. Sci. 83: 699-703, 1994.
438. ULM, E. H., HICHENS, M., GOMEZ, H. J., TILL, A. E., HAND, E., VASSIL, T. C., BIOLLAZ, J., BRUNNER, H. R, AND SCHELLING, J. L.: Enalapril maleate and a lysine analogue (MK-521) disposition in man. Br. J. Clin. Pharmacol. 14: 357-362, 1982.
439. 1-acid glycoprotein, albumin, and nonesterified fatty acids in serum binding of apazone and warfarin. Clin. Pharmacol. Ther. 39: 683-689, 1986.
440. VACCA, J. P., DORSEY, B. D., SCHLEIF, W. A., LEVIN, K. B., MCDANIEL., S. L., DARKE, P. L., ZUGAY, J., QUINTERO, J. C., BLAHY, O. M., ROTH, E., SAKDANA, V. V., SCHLABACH, A. J., GRAHAM, P. I., CONDRA, J. H., GOTLIB, L., HOLLOWAY, M. K., LIN, J. H., CHEN, I-W., VASTAG, K., OSTOVIC, D., ANDERSON, P. S., EMINI, E. A., AND HUFF, J. R.: L-735,524: an orally bioavailable human immunodeficiency virus type-1 protease inhibitor. Proc. Natl. Acad. Sci. USA 91: 4096-4100, 1994.
441. VAN DALES, R., VREE, T. B., BAARS, A. M., AND TERMOND, E.: Dosage adjustment for ceftazidime in patients with impaired renal function. Eur. J. Clin. Pharmacol. 30: 597-605, 1986.
442. VANE, J. R.: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (Lond) 231: 232-235, 1971.
443. VERMEULAN, N. P. E.: Stereoselective biotransformation and its toxicological implications. In Xenobiotic Metabolism and Disposition, ed. by R. Kato, R. W. Estabrook, and M. N. Cayen, pp. 193-206, Taylor & Francis, London, UK, 1989.
444. VESELL, E. S., PASSANANTI, G. T., AND JOHNSON, A. Q.: Failure of indomethacin and warfarin to interact in normal human volunteers. J. Clin. Pharmacol. 15: 486-495, 1975.
445. WALTER, E., AND KISSEL, T.: Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport. Eur. J. Pharm. Sci. 3: 215-230, 1995.
446. WANG, C. Y.: Microsomal amidases and carboxylesterases. In Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity, ed. by F. C. Kauffman, pp. 161-187, Springer-Verlag, Berlin, Germany, 1994.
447. WARD, S., AND BACK, D. J.: Metabolism of gestodene in human liver cytosol and microsomes in vitro. J. Steroid. Biochem. Mol. Biol. 46: 235-243, 1993.
448. WARD, S. A., WALLE, T., WALLE, K., WILKINSON, G. R., AND BRANCH, R. A.: Propranolol's metabolism is determined by both mephenytoin and debrisoquine hydroxylase activities. Clin. Pharmacol. Ther. 45: 72-79, 1989.
449. WATANABE, J., AND KOZAKI, A.: Relationships between partition coefficients and apparent volume of distribution for basic drugs. Chem. Pharm. Bull. 26: 3463-3470, 1978.
450. WATTENBERG, L. W., AND LEONG, J. L.: Inhibition of the carcinogenic action of 7,12-dimethylbenz(a)anthracene by β-naphthofIavone. Proc. Soc. Exp. Biol. Med. 128: 940-943, 1968.
451. WAXMAN, D. J.: Regulation of liver specific steroid metabolizing cytochromes P-450: cholesterol 7α-hydroxylase, bile acid 6β-hydroxylase and growth hormone-responsive steroid hormone hydroxylase. J. Steroid Biochem. Mol. Biol. 43: 1055-1072, 1992.
452. WAXMAN, D. J., DANNAN, G. A., AND GUENGERICH, F. P.: Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry 24: 4409-4417, 1985.
453. WAXMAN, D. J., RAM, P. A., NOTANI, G.. LEBLANC, G. A., ALBERTA, J. A., MORRISSEY, J. J., AND SUNDSETH, S. S.: Pituitary regulation of the male-specific steroid 6β-hydroxylase P-450 2a (gene product IIIA2) in adult rat liver: suppressive influence of growth hormone and thryoxine acting at a pretranslational level. Mol. Endocrinol. 4: 447-454, 1990.
454. WEBB, D. W., RIDDER, G. M., AND ALDEN, C. L.: Acute and subchronic nephrotoxicity of d-limonene in Fischer 344 rats. Food Chem. Toxicol. 27: 639-649, 1989.
455. WEBER, W. W., LEVY, G. N., AND HEIN, D. W.: Acetylation. In Conjugation Reactions in Drug Metabolism, ed. by G. J. Mulder, pp. 163-191, Taylor & Francis, New York, 1990.
456. WECHTER, W. J., LOUGHEAD, D. G., REISCHER, R. J., VAN GIESSEN, G. J., AND KAISER, D. G.: Enzymatic inversion at saturated carbon: nature and mechanism of the inversion of R(-)-p-isobutyl-hydratropic acid. Biochem. Biophy. Ros. Commun. 61: 833-837, 1974.
457. WEINER, I. M., AND MUDGE, G. H.: Inhibitors of tubular transport of organic compounds. In Goodman and Gillman's The Pharmacological Basis of Therapeutics, ed. by A. G. Gillman, L. S. Goodman, T. W. Rall, and F. Murad, 7th ed., pp. 920-925, Macmillan Publishing Company, New York, 1985.
458. WEINER, N.: Drugs that inhibit adrenergic nerves and block adrenorgic receptors. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed. by A. Gilman, L. S. Goodman, T. W. Rall, and F. Murad, 7th ed., pp. 181-214, MacMillan Publishing Company, New York, 1985.
459. WEINER, N., AND TAYLOR, P.: Neurohumoral transmission: the autonomic and somatic motor nervous systems. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed. by A. G. Oilman, L. S. Goodman, T. W. Rall, and F. Murad, 7th ed., pp. 66-99, Macmillan Publishing Company, New York, 1985.
460. WEINSHILBOUM, R. M.: Methyltransferase pharmacogenetics. In Pharmacogenetics of Drug Metabolism, ed. by W. Kalow, pp. 179-194, Pergamon Press, New York, 1992.
461. WEINSHILBOUM, R. M., AND SLADEK, S. L.: Mercaptopurine pharmacogenetics: monogenetic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32: 651-662, 1980.
462. WEISBRODT, N. W.: Motility of the small intestine. In Physiology of Gastrointestinal Tract, ed. by L. R. Johnson, pp. 031-663, Raven Press, New York, 1987.
463. WEISER, M. M.: Intestinal epithelial cell surface membrane glycoprotein synthesis: I - an indicator of cellular differentiation. J. Biol. Chem. 248: 2536-2541, 1973.
464. WELLING, P. G., HUANG, H., KOCH, P. A., CRAIG, W. A., AND MADSEN, P, O.: Bioavailability of ampicillin and amoxicillin in fasted and non-fasted subjects. J. Pharm. Sci. 66: 549-552, 1977.
465. WERMUTH, C. G.: Designing prodrugs and bioprecursors. In Drug Design: Fact or Fantasy?, ed. by G. Jolles and K. R. H. Woolbridge, pp. 47-72, Academic Press, New York, 1984.
466. WHITLOCK, J. P., OKINO, S. T., DOUG, L., KO, H. P., CLARKE-KATZENBERG, R., MA, Q., AND LI, H.: Induction of cytochrome P4501A1: a model for analyzing mammalian gene transcription. FASEB J. 10: 809-818, 1996.
467. WILK, S., MIZOGUCHI, H., AND ORLOWSKI, M.: γ-Glutamyl dopa: a kidney-specific dopamine precursor. J. Pharmacol. Exp. Ther. 206: 227-232, 1978.
468. WILKINSON, G. R.: Clearance approaches in pharmacology. Pharmacol. Rev. 38: 1-47, 1987.
469. WILKINSON, G. R., GUENGERICH, F. P., AND BRANCH, R. A.: Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol. Ther. 43: 53-76, 1989.
470. WILKINSON, G. R., GUENGERICH, F. P., AND BRANCH, R. A.: Genetic polymorphism of S-mephenytoin hydroxylation. In Pharmacogenetics of Drug Metabolism, ed. by W. Kalow, pp. 657-685, Pergamon Press, New York, 1992.
471. WILKINSON, G. K., AND SHAND, D. G.: A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18: 377-390, 1975.
472. WILLIAMS, K., AND LEE, E.: Importance of drug enantiomers in clinical pharmacology. Drugs 30: 333-354, 1985.
473. WILLIAMS, M., AND OLSEN, R. W.: Benzodiazepine receptors and tissue function. In Receptor Pharmacology and Function, ed. by M. William, R. A. Glennon, and P. B. Timmermans, pp. 385-413, Marcel Dekker, New York, 1989.
474. WILSON, C. G., WASHINGTON, C., AND WASHINGTON, N.: Overview of epithelial barriers and drug transport. In Physiological Pharmaceutics: Biological Barriers to Drug Absorption, ed. by C. G. Wilson and N. Washington, pp. 11-20, Ellis Horwood Limited, Chichester, UK, 1989.
475. WILSON, G., HASSAN, I. F., DIX, C. J., WILLIAMSON, I., SHAH, R., MACKAY, M., AND ARTURSSON, P.: Transport and permeability properties of human Caco-2 cells: an in vitro model of the intestinal epithelial cell barrier. J. Controlled Release 11: 25-40, 1990.
476. WILSON, K.: Sex-related differences in drug disposition in man. Clin. Pharmacokinet. 9: 189-202, 1984.
477. WINDMUELLER, H. G., AND SPAETH, A. E.: Intestinal metabolism of glutamine and glutamate from the lumen as compared to glutamine from blood. Arch. Biochem. Biophys. 171: 662-672, 1975.
478. WONG, B. K., BRUTHIN, P. J., BARRISH, A., AND LIN, J. H.: Nonlinear dorzolamide pharmacokinetics in rats: concentration dependent erythrocyte distribution and drug-metabolite displacement interaction. Drug Metab. Dispos. 24: 659-663, 1996.
479. WOOD, A. J. J., KORNHAUSER, D. M., WILKINSON, G. R., SHAND, D. G., AND BRANCH, R. A.: The influence of cirrhosis on steady-state blood concentration of unbound propranolol after oral administration. Clin. Pharmacokinet, 3: 478-487, 1978.
480. WOODSON, I., C., DUNNETTE, J. H., AND WEINSHILBOUM, R. M.: Pharmacogenetics of human thiopurine methyltransferase: kidney-erythrocyte correlation and immunotitration studies. J. Pharmacol. Exp. Ther. 222: 174-181, 1982.
481. WORBOYS, P. D., BRADBURY, A., AND HOUSTON, B.: Kinetics of drug metabolism in rat liver slices: II - comparison of clearance by liver slices und freshly isolated hepatocytes. Drug Metab. Dispos. 24: 676-681, 1996.
482. WRIGHTON, S. A., AND RING, B. J.: Inhibition of human CYP3A catalyzed 1′-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine and nizatidine. Pharm. Res. 11: 921-924, 1994.
483. WRICHTON, S. A., AND STEVENS, J. C.: The human hepatic cytochrome P450 involved in drug metabolism. CRC Crit. Rev. Toxicol 22: 1-21, 1992
484. WRIGHTON, S. A., VANDENBRANDEN, M., STEVENS, J. C., SHIPLEY, L. A., RING, B. J., RETTIE, A. E., AND CASHMAN, J. R.: In vitro methods for assessing human hepatic drug metabolism: their use in drug development. Drug Metab. Rev. 25: 453-484, 1993.
485. YACOBI, A., AND LEVY, G.: Effect of plasma protein binding on the anticoagulant action of warfarin in rate. Res. Commun. Chem. Pathol. Pharmacol. 12: 405-408, 1975.
486. YACOBI, A., AND LEVY, G.: Frequency distribution of free warfarin and free phenytoin fraction values in serum of healthy human adults. Clin. Pharmacol. Ther. 21: 283-286, 1977.
487. YACOBI, A., UDALI., J. A., AND LEVY, G.: Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect. Clin. Pharmacol. Ther. 19: 552-558, 1976.
488. YASUMORI, T., CHEN, L., NAGATA, K., YAMAZOE, Y., AND KATO, R.: Species differences in stereosclective metabolism of mephenytoin by cytochrome P-450 (CYP 2C and CYP 3A). J. Pharmacol. Exp. Ther. 264: 89-94, 1993a.
489. YASUMORI, T., NAGATA, K., YANG, S. K., CHEN, L-S., Murayama, N., Yamazoe, Y., and Kato, R.: Cytochrome P-450 mediated metabolism of diazepam in human and rat: involvement of human CYP 2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogentics 3: 291-301, 1993b.
490. YEE, G. C., AND MCGUIRE, T. R.: Pharmacokinetic drug interactions with cyclosporin: part I. Clin. Phormacokinet. 19: 319-332, 1990.
491. YUN, C. H., LEE, H. S., LEE, H., RHO, J. K., JEONG, H. G., AND GRUENGERICH, F. P.: Oxidation of the angiotengin II receptor antagonist losartan (DuP 753) in human liver microsomes: role of cytochrome P-4503A(4) in formation of the active metabolite Exp3174. Drug Metab. Dispos. 23: 285-289, 1995.
492. YUN, C. H., OKERHOLM, R. A., AND GUENGERICH, F. P.: Oxidation of the antihistaminic drug terfenadine in human liver microsomes: role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation. Drug Metab. Dispos. 21: 403-409, 1993.
493. ZHANG, K., TANG, C., RASHED, M., CUI, D., TOMBRET, K., BOTTE, H., LEPAGE, F., LEVY, R. H., AND BAILLIE, T. A.: Metabolic chiral inversion of stiripentol in the rat: I-mechanistic studies. Drug Metab. Dispos. 22: 544-553, 1994.
494. ZINI, R., D'ATHIS, P., BARRE, J., AND TILLEMENT, J. P.: Binding of indomethacin to human serum albumin: its non-displacement by various agents, influence of free fatty acid and the unexpected effect of indomethacin on warfarin binding. Biochem Pharmacol. 28: 2661-2665, 1979.