Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport

Annual Review of Pharmacology and Toxicology

Volumn 38, Issue , 1998, Pages 461-499

  Ito, K ^a   Iwatsubo, T ^b   Kanamitsu, S ^a   Nakajima, Y ^a   Sugiyama, Y ^a  

^a UNIVERSITY OF TOKYO   (Japan)

^b ASTELLAS PHARMA INC   (Japan)

Author keywords

Clearance concept; Cytochrome P450; In vitro in vivo extrapolation; Metabolic inhibition; Physiological model

Indexed keywords

BENZODIAZEPINE; CYCLOSPORIN; CYTOCHROME P450; DIAZEPAM; ERYTHROMYCIN; KETOCONAZOLE; METOPROLOL; OMEPRAZOLE; RIFAMPICIN; SULFAPHENAZOLE; TERFENADINE; TOLBUTAMIDE; TRIAZOLAM;

AREA UNDER THE CURVE; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG TRANSPORT; GASTROINTESTINAL ABSORPTION; HUMAN; IN VITRO STUDY; LIVER CLEARANCE; LIVER METABOLISM; LIVER MICROSOME; METABOLIC CLEARANCE RATE; METABOLIC INHIBITION; PREDICTION; PRIORITY JOURNAL; REVIEW;

EID: 0031777718     PISSN: 00664251     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.38.1.461     Document Type: Review

References (109)

1. Dedrick RL. 1973. Animal scale-up. J. Pharmacokinet. Biopharm. 1:435-61
2. Boxenbaum H. 1982. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm. 10:201-27
3. Sawada Y, Hanano M, Sugiyama Y, Iga T. 1984. Prediction of the disposition of β-lactam antibiotics in human from pharmacokinetic parameters in animals. J. Pharmacokinet. Biopharm. 12:241-61
4. Boxenbaum H. 1980. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance extra-polation of data to benzodiazepines and phenytoin. J. Pharmacokinet. Biopharm. 8:165-76
5. Lin JH. 1995. Species similarities and differences in pharmacokinetics. Drug Metab. Dispos. 23:1008-21
6. Izumi T, Enomoto S, Hosiyama K, Sasahara K, Shibukawa A, et al. 1996. Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J. Pharmacol. Exp. Ther. 277:1630-41
7. Rane A, Wilkinson GR, Shand DG. 1977. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J. Pharmacol. Exp. Ther. 200:420-24
8. Wilkinson GR. 1987. Clearance approaches in pharmacology. Pharmacol. Rev. 39:1-47
9. Sugiyama Y, Sawada Y, Iga T, Hanano M. 1988. Xenobiotic metabolism and disposition. In Proc. 2nd Int. ISSX Meet., ed. R Kato, RW Estabrook, MN Cayen, pp. 225-35. London: Taylor & Francis
10. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Sugiyama Y. 1996. Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics. Biopharm. Drug Dispos. 17:273-310
11. Suzuki H, Iwatsubo T, Sugiyama Y. 1995. Applications and prospects for physiologically based pharmacokinetic (PB-PK) models involving pharmaceutical agents. Toxicol. Lett. 82/83:349-55
12. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Shimada N, et al. 1997. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol. Ther. 73:147-71
13. Rowland M, Tozer TN. 1995. Interacting drugs. In Clinical Pharmacokinetics, pp. 267-89. Philadelphia: Lea & Febiger. 3rd ed.
14. Sugiyama Y, Iwatsubo T. 1996. Alteration of pharmacokinetic features caused by drug interactions. Xenobio. Metabol. Dispos. 11:286-93
15. Sugiyama Y, Iwatsubo T, Ueda K, Ito K. 1996. Strategic proposals for avoiding toxic interactions with drugs for clinical use during development and after marketing of a new drug: pharmacokinetic consideration. J. Toxicol Sci. 21:309-16
16. Lin JH, Hayashi M, Awazu S, Hanano M. 1978. Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat. J. Pharmacokinet. Biopharm. 6:327-37
17. Lin JH, Sugiyama Y, Awazu S, Hanano M. 1980. Kinetic studies on the deethylation of ethoxybenzamide: a comparative study with isolated hepatocytes and liver microsomes of rat. Biochem. Pharmacol. 29:2825-30
18. Yasumori T, Nagata K, Yang SK, Chen LS, Murayama N, et al. 1993. Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 3:291-301
19. Kato R, Yamazoe Y. 1994. The importance of substrate concentration in determining cytochromes P450 therapeutically relevant in vivo. Pharmacogenetics 4:359-62
20. Klotz U, Antonin KH, Bieck PR. 1976. Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. J. Pharmacol. Exp. Ther. 199:67-73
21. Seddon T, Michelle I, Chenery RJ. 1989. Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog. Biochem. Pharmacol. 38:1657-65
22. Grant MH, Burke MD, Hawksworth GM, Duthie SJ, Engeset J, et al. 1987. Human adult hepatocytes in primary monolayer culture. Maintenance of mixed function oxidase and conjugation pathways of drug metabolism. Biochem. Pharmacol. 36:2311-16
23. Bayliss MK, Bell JA, Jenner WN, Wilson K. 1990. Prediction of intrinsic clearance of loxtidine from kinetic studies in rat, dog and human hepatocytes. Biochem. Soc. Trans. 18:1198-99
24. Broly F, Libersa C, Lhermitte M. 1990. Mexiletine metabolism in vitro by human liver. Drug Metab. Dispos. 18:362-68
25. Robson RA, Matthews AP, Miners JO, McManus ME, Meyer UA, et al. 1987. Characterisation of theophylline metabolism in human liver microsomes. Br. J. Clin. Pharmacol. 24:293-300
26. Jacolot F, Simon I, Dreano Y, Beaune P, Riche C, et al. 1991. Identification of cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. Biochem. Pharmacol. 41:1911-19
27. Richard B, Fabre G, Sousa GD, Fabre I, Rhamani R, et al. 1991. Interspecies variability in mitoxantrone metabolism using primary cultures of hepatocytes isolated from rat, rabbit and human. Biochem. Pharmacol. 41:255-62
28. Rowland M, Benet LZ, Graham G. 1973. Clearance concepts in pharmacokinetics. J. Pharmacokinet. Biopharm. 1:123-36
29. Wilkinson GR, Shand DG. 1975. A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18:377-90
30. Pang KS, Rowland M. 1977. Hepatic clearance of drugs: I. Theoretical consid-erations of a "well-stirred" model and a "parallel-tube" model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. J. Pharmacokinet. Biopharm. 5:625-53
31. Pang KS, Rowland M. 1977. Hepatic clearance of drugs. II. Experimental evidence for acceptance of the "well-stirred" model over the "parallel-tube" model using lidocaine in the perfused rat liver in situ preparation. J. Pharmacokinet. Biopharm. 5:655-80
32. Winkler K, Keiding S, Tygstrup N. 1973. The liver. In Quantitative Aspects of Structure and Function, ed. G Paumgartner, R Preisig, pp. 144-55. Basel: Karger
33. Bass L, Keiding S. 1988. Physiologically based models and strategic experiments in hepatic pharmacology. Biochem. Pharmacol. 37:1425-31
34. Bass L, Robinson P, Bracken AJ. 1978. Hepatic elimination of flowing substrates: the distributed model. J. Theor. Biol. 72:161-84
35. Roberts MS, Rowland M. 1986. A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations. J. Pharmacokinet. Biopharm. 14:227-60
36. Roberts MS, Rowland M. 1986. Correlation between in vitro microsomal enzyme activity and whole organ hepatic elimination kinetics: analysis with a dispersion model. J. Pharm. Pharmacol. 38:177-81
37. Roberts MS, Donaldson JD, Rowland M. 1988. Models of hepatic elimination: comparison of stochastic models to describe residence time distributions and to predict the influence of drug distribution, enzyme heterogeneity, and systemic recycling on hepatic elimination. J. Pharmacokinet. Biopharm. 16:41-83
38. Pang KS, Chiba M. 1994. Metabolism: scaling-up from in vitro to organ and whole body. In Handbook of Experimental Pharmacology, ed. PG Welling, LP Balaut, pp. 101-87. New York: Springer-Verlag
39. Ahmad AB, Bennett PN, Rowland M. 1983. Models of hepatic drug clearance: discrimination between the "well-stirred" and "parallel-tube" models. J. Pharm. Pharmacol. 35:219-24
40. von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, et al. 1996. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J. Pharmacol. Exp. Ther. 276:370-79
41. Eberts FS Jr, Philopoulos Y, Reineke LM, Vliek RW. 1981. Triazolam disposition. Clin. Pharmacol. Ther. 29:81-93
42. Bischoff KB, Dedrick RL, Zaharko DS, Longstreth JA. 1971. Methotrexate pharmacokinetics. J. Pharm. Sci. 60:1128-33
43. Montandon B, Roberts RJ, Fischer LJ. 1975. Computer simulation of sulfobromophthalein kinetics in the rat using flow-limited models with extrapolation to man. J. Pharmacokinet. Biopharm. 3:277-90
44. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI. 1994. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br. J. Clin. Pharmacol. 38:23-31
45. Smith RB, Kroboth PD, Vanderlugt JT, Phillips JP, Juhl RP. 1984. Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration. Psychopharmacology 84:452-56
46. 14C-alprazolam, a new anxiolytic-antidepressant, in man. Pharmacologist 22: 279
47. Kim M, Shen DD, Eddy AC, Nelson WL. 1992. Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. Drug Metab. Dispos. 21:309-17
48. Schaaf LJ, Cambell SC, Mayersohn MB, Vagedes T, Perrier DG. 1987. Influence of smoking and gender on the disposition kinetics of metoprolol. Eur. J. Clin. Pharmacol. 33:355-61
49. Regardh CG, Borg KO, Johansson R, Palmer L. 1974. Pharmacokinetics studies on the selective β1-receptor antagonist metoprolol in man. J. Pharmacokinet. Biopharm. 2:347-64
50. Johansson KA, Appelgern C, Borg KO, Elofsson R. 1974. Binding of two adrenergic beta-receptor antagonists, alprenolol and H 93/26, to human serum proteins. Acta Pharm. Suec. 11:333-46
51. Quarterman CP, Kendall MJ, Jack DB. 1981. The effect of age on the pharmacokinetics of metoprolol and its metabolites. Br. J. Clin. Pharmacol. 11:287-94
52. De Waziers I, Cugnenc PH, Yang CS, Leroux J-P, Beaune PH. 1990. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferees in rat and human hepatic and extrahepatic tissues. J. Pharmacol. Exp. Ther. 253:387-94
53. Wu C-Y, Benet LZ, Hebert MF, Gupta SK, Rowland M, et al. 1995. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin. Pharmacol. Ther. 58:492-97
54. Miyauchi S, Sugiyama Y, Sawada Y, Morita K, Iga T, et al. 1987. Kinetics of hepatic transport of 4-methylumbelliferone in rats: analysis by multiple indicator dilution method. J. Pharmacokinet. Biopharm. 15:25-38
55. Yamazaki M, Suzuki H, Sugiyama Y. 1996. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm. Res. 13:497-513
56. Thummel KE, Shen DD, Podoll T, Kunze KL, Trager WF, et al. 1994. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J. Pharmacol. Exp. Ther. 271:549-56
57. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. 1994. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270:414-22
58. Sugiyama Y, Iwatsubo T. 1994. Physiological pharmacokinetics: prediction of human drug disposition and pharmacokinetics from animal data and from in vitro to in vivo. In Proc. Int. Symp. Role Drug Metab. Pharmacokinet. Res. New Drug Dev., pp. 45-63. Doping Control Center, Korea Inst. Sci. Technol. (KIST)
59. Hoener B-A. 1994. Predicting the hepatic clearance of xenobiotics in humans from in vitro data. Biopharm, Drug Dispos. 15:295-304
60. Houston JB. 1994. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47:1469-79
61. Ashforth EIL, Carlile DJ, Chenery R, Houston JB. 1995. Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data. J. Pharmacol. Exp. Ther. 274:761-66
62. Hayes KA, Brennan B, Chenery R, Houston JB. 1995. In vivo disposition of caffeine predicted from hepatic microsomal and hepatocyte data. Drug Metab. Dispos. 23:349-53
63. Iwatsubo T, Suzuki H, Shimada N, Chiba K, Ishizaki T, et al. 1997. Prediction of in vivo hepatic metabolic clearance of YM796 from in vitro data by use of human liver microsomes and recombinant P-450 isozymes. J. Pharmacol. Exp. Ther. 282:909-19
64. Iwatsubo T, Suzuki H, Sugiyama Y. 1997. Prediction of species differences (rats, dogs, humans) in the in vivo metabolic clearance of YM796 by the liver from in vitro data. J. Pharmacol. Exp. Ther. 283:462-69
65. Iwatsubo T, Hisaka A, Suzuki H, Sugiyama Y. 1997. Prediction of in vivo non-linear first-pass hepatic metabolism of YM796 from in vitro metabolic data. J. Pharmacol. Exp. Ther. Submitted
66. Renaud J-P, Cullin C, Pompon D, Beaune P, Mansuy D. 1990. Expression of human liver cytochrome P450IIIA4 in yeast: a functional model for the hepatic enzyme. Eur. J. Biochem. 194:889-96
67. Crespi CL. 1995. Xenobiotic-metabolizing human cells as tools for pharmacological and toxicological research. Adv. Drug Res. 26:179-235
68. Kobayashi K, Chiba K, Yagi T, Shimada N, Taniguchi T, et al. 1997. Identification of cytochrome P450 isoforms involved in citalopram W-demethylation by human liver microsomes. J. Pharmacol. Exp. Ther. 280:927-33
69. Rane A, Sawe J, Lindberg B, Svensson JO, Garle M, et al. 1984. Morphine glucuronidation in the rhesus monkey: a comparative in vivo and in vitro study. J. Pharmacol. Exp. Ther. 229:571-76
70. Mistry M, Houston JB. 1987. Glucuronidation in vitro and in vivo: comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab. Dispos. 15:710-17
71. Izumi T, Hosiyama K, Enomoto S, Sasahara K, Sugiyama Y. 1997. Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data. J. Pharmacol. Exp. Ther. 280:1392-400
72. Oberle RL, Chen T-S, Lloyd C, Barnett JL, Owyang C, et al. 1990. The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. Gastroenterohgy 99:1275-82
73. Rowland M, Martin SB. 1973. Kinetics of drug-drug interactions. J. Pharmacokin. Biopharm. 1:553-67
74. Tucker GT. 1992. The rational selection of drug interaction studies: implications of recent advances in drug metabolism. Int. J. Clin. Pharmacol. Ther. Toxicol. 30:550-53
75. Christensen LK, Hansen JM, Kristensen M. 1963. Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet 2:1298-301
76. Veronese ME, Miners JO, Randles D, Gregov D, Birkett DJ. 1990. Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers. Clin. Pharmacol. Ther. 47:403-11
77. Thomas RC, Ikeda GJ. 1966. The metabolic fate of tolbutamide in man and in the rat. J. Med. Chem. 9:507-10
78. Nelson E, O'Reilly I. 1961. Kinetics of carboxytolbutamide excretion following tolbutamide and carboxytolbutamide administration. J. Pharmacol. Exp. Ther. 132:103-9
79. Miners JO, Smith KJ, Robson RA, McManus ME, Veronese ME, et al. 1988. Tolbutamide hydroxylation by human liver microsomes. Biochem. Pharmacol. 37:1137-44
80. Back DJ, Tjia JF, Karbwang J, Colbert J. 1988. In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulfonamides and quinolines. Br. J. Clin. Pharmacol. 26:23-29
81. Biglin KE, Faraon MS, Constance TD, Lieh-Lai M. 1994. Drug-induced torsades de pointes: a possible interaction of terfenadine and erythromycin. Ann. Pharmacother. 28:282
82. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, et al. 1990. Torsades de pointes occurring in association with terfenadine use. JAMA 264:2788-90
83. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, et al. 1993. Terfenadine-ketoconazole interaction. JAMA 269:1513-18
84. Garteiz DA, Hook RH, Walker BJ, Okerholm RA. 1982. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneim.-Forsch./Drug Res. 32:1185-90
85. von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Shader RI. 1994. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J. Clin. Pharmacol. 34:1222-27
86. Daneshmend TK, Warnock DW, Turner A, Roberts CJC. 1981. Pharmacokinetics of ketoconazole in normal subjects. J. Antimicrob. Chemother. 8:299-304
87. Daneshmend TK, Warnock DW, Ene MD, Johnson EM, Potten MR, et al. 1984. Influence of food on the pharmacokinetics of ketoconazole. Antimicrob. Agents Chemother. 25:1-3
88. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Duan SX, Harmatz JS, et al. 1994. Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J. Pharmacol. Exp. Ther. 268:1278-83
89. von Moltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, et al. 1995. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J. Clin. Psychopharmacol. 15:125-31
90. von Moltke LL, Greenblatt DJ, Schmider J, Harmatz JS, Shader RI. 1995. Metabolism of drugs by cytochrome P450 3A isoforms. Implications for drug interactions in psychopharmacology. Clin. Pharmacokin. 29:33-43 (Suppl.)
91. von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Wright CE, et al. 1996. Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo. J. Clin. Psychopharmacol. 16:104-12
92. Gugler R, Jansen JC. 1985. Omeprazole inhibits oxidative drug metabolism. Gastroenterology 89:1235-41
93. Chiba K, Kobayashi K, Manabe K, Kamataki T, Ishizaki T. 1993. Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephemytoin 4′-hydroxylation. J. Pharmacol. Exp. Ther. 266:152-59
94. Cederberg C, Andersson T, Skanberg I. 1989. Omeprazole: pharmacokinetics and metabolism in man. Scand. J. Gastroenterol. 66:33-40
95. Zomorodi K, Houston JB. 1995. Effect of omeprazole on diazepam disposition in the rat: in vitro and in vivo studies. Pharm.Res. 12:1642-46
96. Periti P, Mazzei T, Mini E, Novelli A. 1992. Pharmacokinetic drug interactions of macrolides. Clin. Pharmacokinet. 23:106-31
97. Yamazaki M, Nishigaki R, Suzuki H, Sugiyama Y. 1995. Kinetic analysis of hepatobiliary transport of drugs: importance of carrier-mediated transport. Yakugaku Zasshi 115:953-77
98. +-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am. J. Physiol. 264:G36-G44
99. 2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of Type 1 system. J. Pharmacol. Exp. Ther. 269:1220-27
100. Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP. 1991. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology 101:1680-91
101. Transon C, Leemann T, Dayer P. 1996. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur. J. Clin. Pharmacol. 50:209-15
102. Kolars JC, Awni WM, Merion RM, Watkins PB. 1991. First-pass metabolism of cyclosporin by the gut. Lancet 338: 1488-90
103. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. 1992. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 90:1871-78
104. Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, et al. 1996. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin. Phamracol. Ther. 59:491-502
105. Saitoh H, Aungst BJ. 1995. Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine. Pharm. Res. 12:1304-10
106. Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A. 1996. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorpti J. Pharm. Pharmacol. 48:1083-89
107. Wacher VJ, Wu C-Y, Benet LZ. 1995. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog. 13:129-34
108. Benet LZ. 1995. Interspecies scaling: new lessons utilizing metabolic isozymes and pharmacokinetics. Int. Symp. Strategy Drug Metab. Study New Drug Dev. Tokyo, June 13-15, pp. 43-46
109. Benet LZ. 1996. Problems and progress: from Bio-International '89 to the present. FIP Bio-International '96. Tokyo, April 22-24, pp. 9-13