Kinetics of reactive phase II metabolites: Stereochemical aspects of formation of epimeric acyl glucuronides and their reactivity

Chemical Analysis

Volumn 142, Issue , 1997, Pages 125-171

  Spahn Langguth, Hildegard ^a   Benet, Leslie Z ^b   Zia Amirhosseini, Parnian ^b   Iwakawa, Seigo ^c   Langguth, Peter ^d  

^a MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c KOBE UNIVERSITY   (Japan)

^d ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0142222328     PISSN: 00692883     EISSN: None     Source Type: Book Series    
DOI: None     Document Type: Article

References (133)

1. Advenier, C., Roux, A., Gobert, C., Massias, P., Varoquaux, O., and Flouvat, B. (1983). Pharmacokinetics of ketoprofen in the elderly. Br. J. Clin. Pharmac., 16, 65-70.
2. Amos, H. E, Wilson, D. V, Taussig, M. J., and Carlton, S. J. (1971). Hypersensitivity reactions to acetylsalicylic acid. Clin. Exp. Immunol., 8, 563-572.
3. Anttila, M., Haataja, M., and Kasanan, A. (1980). Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur. J. Clin. Pharmacol., 18, 263-268.
4. Arima, N. (1990). Acyl glucuronidation and glucosidation of pranoprofen, a 2-arylpropionic acid derivative, in mouse liver and kidney homogenates. J. Pharmacobio.-Dyn., 13, 724-732.
5. Arima, N. (1990). Stereoselective acyl glucuronidation and glucosidation of pranoprofen, a 2-arylpropionic acid derivative, in mice in vivo. J. Pharmacobio.-Dyn., 13, 733-738.
6. Bakke, O. M., Wardell, W. M., and Lasagna, L. (1984). Drug discontinuations in the United Kingdom and the United States: 1964-1983. Clin. Pharmacol. Ther., 35, 559-567.
7. Benet, L. Z. and Spahn, H. (1988). Acyl migration and covalent binding of drug glucuronides - potential toxicity mediators. In G. Siest, J. Magdalou, B. Burchell (eds.) Molecular and Cellular Aspects of Glucuronidation, Colloques INSERM/John Libbey Eurotext, Vol. 173, London: pp. 261-269.
8. Benet, L. Z., Bisher, A., Volland, C., Spahn-Langguth, H. (1992). The pharmaco- and toxicokinetics of reactive and active phase II metabolites. In D. J. A. Crommelin, K. K. Midha (eds.), Topics in Pharmaceutical Sciences, Med. Pharm. Scientific Publishers, Stuttgart, 533-544.
9. Benet, L. Z., Spahn-Langguth, H., Iwakawa, S., Volland, C., Mizuma, T., Mayer, S., Mutschler, E., and Lin, E. T. (1993). Prediction of covalent binding of acidic drugs in man. Life Sci., 53, PL141-146.
10. Bischer, A., Zia-Amirhosseini, P., Iwaki, M., McDonagh, A. F., and Benet, L. Z. (1995). Stereoselective binding properties of naproxen glucuronide diastereomers to proteins. J. Pharmacokinet. Biopharm. (in press).
11. Blanckaert, N., Compernolle, F., Leroy, P., Van Hautte, R., Fevery, J., and Heirwegh, K. P. M. (1978). The fate of bilirubin-IXα glucuronide in cholestasis and during storage in vitro. Biochem. J., 171, 203-214.
12. 9-11-carboxytetrahydrocannabinol glucuronide. Chem. Res. Toxicol., 2, 316-324.
13. Brockmeier, D. and Ostrowski, J. (1985). Mean-time and first-pass metabolism Eur. J. Clin. Pharmacol., 29, 45-48.
14. Brockmeier, D., Hajdu, P., Henke., W., Mutschler, E., Palm, D., Rupp, W., Spahn, H., Verho, M. T., and Wellstein, A. (1988). Pharmacokinetics of penbutolol, its effect on exercise heart rate and in vitro inhibition of radioligand binding using plasma samples Eur. J. Clin. Pharmacol., 29, 45-48.
15. Burchell, B. and Coughtrie, M. W. H. (1989). UDP-glucuronosyltransferases. Pharmacol. Ther., 43, 261-289.
16. Buszewski, B., el Mouelhi, M., Albert, K., and Bayer, E. (1990). Influence of the structure of chemically bonded C18 phases on HPLC separation of naproxen glucuronide diastereomers. J. Liq. Chromatogr., 13, 505-524.
17. Castillo, M., and Smith, P. C. (1995). Disposition and reactivity of ibuprofen and ibufenac acyl glucuronides in vivo in the Rhesus monkey and in vitro, with human, serum albumin. Drug Metab. Disp., 23, 566-572.
18. Chakir, S., Maurice, M. H., Magdalou, J., Leroy, P., Dubois, N., Lapicque, F., Abdelhamid, Z., and Nicolas, A. (1994). High-performance liquid chromatographic enantioselective assay for the measurement of ketoprofen glucuronidation by liver microsomes, J. Chromatogr., 654, 61-68.
19. Chan, K. K. H. and Gibaldi, M. (1990). Effects of first-pass metabolism on metabolite mean residence time determination after oral administration of parent drug. Pharm. Res., 7, 59-63.
20. Cox, J. W., Cox, S. R., VanGiessen, G., and Ruwart, M. J. (1985). Ibuprofen stereoisomer hepatic clearance and distribution in normal and fatty in situ perfused rat liver. J. Pharmacol. Exp. Ther., 232, 636-643.
21. Dahms, M. and Spahn-Langguth, H. (1995). Acyl glucuronides as reactive intermediates: Detection of flunoxaprofen protein adducts in biological material. Naunyn Schmiedeberg's Arch. Pharmacol., 351 (suppl.), R5.
22. Dahms, M. and Spahn-Langguth, H., (1996). Covalent binding of acidic drugs via reactive intermediates: Detection of benoxaprofen and flunoxaprofen adducts in biological material. Die Pharmazie (in press).
23. Dickinson, R. G. and King, A.R. (1993). Studies on the reactivity of acyl glucuronides-V. Glucuronide-derived covalent binding of diflunisal to bladder tissue of rats and its modulation by urinary pH and β-glucuronidase. Biochem. Pharmacol., 46, 1175-1182.
24. Ding, A., Ojingwa, J.C., McDonagh, A.F., Burlingame, A.L., and Benet, L. Z. (1993). Evidence for covalent binding of acyl glucuronides to serum albumin via an imine mechanism as revealed by tandem mass spectrometry. Proc. Nat. Acad. Sci. USA, 90, 3797-3801.
25. Ding, A., Zia-Amirhosseini, P., McDonagh, A. F., Burlingame, A. L., and Benet, L. Z. (1995). Reactivity of tolmetin glucuronide with human serum albumin: Identification of binding sites and mechanisms of reaction by tandem mass spectrometry. Drug Metab. Disp., 23, 369-376.
26. Dressman, J. B., Beradi, R. R., Elta, G. H., Gary, T. M., Montgomery, P. A., Lau, H. S., Pelekoudas, K. L., Szpunar, H. S., and Wagner, J. G. (1992). Absorption of flurbiprofen in the fed and fasted state. Pharm. Res., 9, 901-907.
27. Dubois, N., Lapicque, F., Maurice, M. H., Pritchard, M., Fournel-Gigleux, S., Magdalou, J., Abiteboul, M., Siest, and G., Netter, P., (1993). In vitro irreversible binding of ketoprofen glucuronide to plasma proteins. Drug Metab. Disp., 21, 617-623.
28. Dudley. K. H. (1985). Commentary: Stereochemical formulas of β-D-glucuronides. Drug Metab. Disp., 13, 524-528.
29. el Mouelhi, M., Ruelius, H. W., Fenselau, C., and Dulik, D. M. (1988). Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids: Naproxen, ibuprofen and benoxaprofen. Drug Metab. Disp., 16, 627-634.
30. el Mouelhi, M. and Schwenk, M. (1991). Stereoselective glucuronidation of naproxen in isolated cells from liver, stomach, intestine, and colon of the guinea pig. Drug Metab. Disp., 19, 844-845.
31. Faed, E. M. (1984). Properties of acyl glucuronides: Implications for studies of the pharmacokinetics and metabolism of acidic drugs. Drug Metab. Rev., 15, 1213-1249.
32. Foster, R. T., Jamali, F., and Russell, A. S. (1989). Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: Influence of probenecid. Eur. J. Clin Pharmacol., 37, 589-594.
33. Fournel-Gigleux, S., Hamar-Hansen, C., Motassim, N., Antoine, B., Mothe, O., Decolin D., Caldwell, J., and Siest, G. (1988). Substrate-specificity and enantio-selectivity of arylcarboxylic acid glucuronidation. Drug Metab. Disp., 16, 627-634.
34. Fournel-Gigleux, S., Magdalou, J., Lafaurie, C., Siest, G., Grislain, L., Garnier, M. H., Dabé, J. F., Luijten, W., Bromet, N., and Devissaget, M. (1988). Glucuronidation of perindopril by hepatic microsomes: Interspecies comparison, In G. Siest, J. Magdalou, and B. Burchell (eds.), Molecular and Cellular Aspects of Glucuronidation, Colloques INSERM/John Libbey Eurotext, Vol. 173, London pp. 305-309.
35. Geisslinger, G., Ferreira, S. H., Menzel, S., Schlott, D., and Brune, K. (1994). Antinociceptive actions of R (-)-flurbiprofen - a non-cyclooxygenase inhibiting 2-arylpropionic acid - in rats. Life Sci., 54, PL173-177.
36. Grahnen, A., Hammarlund, M., and Lundquist, T. (1984). Implications of intraindividual variability in bioavailability studies of furosemide. Eur. J. Clin. Pharmacol., 27, 595-602.
37. Grubb, N., Caldwell, J., and Strolin-Benedetti, M. (1993). Excretion balance and urinary metabolism of indobufen in rats and mice. Biochem. Pharmacol., 46, 759-761.
38. Grubb, N., Weil, A., and Caldwell, J. (1993). Studies on the in vitro reactivity of clofibryl and fenofibryl glucuronides. Evidence for protein binding via a Schiff's base mechanism. Pharmacology., 46, 357-364.
39. Gugler, R., Kurten, J. W., Jensen, C. J., Klehr, U., Hartlapp, J. (1979). Clofibrate disposition in renal failure and acute and chronic liver disease. Eur. J. Clin. Pharmacol., 230, 237-241.
40. 14C] glucuronic acid. J. Chromatogr., 383, 51-60.
41. Hammarlund, M. M., Paalzow, L. K., and Odlind, B. (1984). Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur. J. Clin. Pharmacol., 26, 197-207.
42. Hargus, S. J., Martin, B. M., and Pohl, L. R. (1995). Covalent modification of rat liver dipeptidyl peptidase IV by diclofenac metabolites. The International Symposium on Biological Reactive Intermediates, Munich, Jan. 1995, abstract vol., p. 74.
43. Hasegawa, J., Smith, P. C., and Benet, L. Z. (1982). Apparent intramolecular acyl migration of zomepirac glucuronide. Drug Metab. Disp., 10, 469-473.
44. von Hattingberg, H. M., and Brockmeier, D. (1982). A concept for the assessment of bioavailability in complex systems in terms of amounts and rates. In G. Bozler, and J. M. van Rossum (eds.), Pharmacokinetics During Drug Development: Data Analysis and Evaluation Techniques, Stuttgart: G. Fischer Verlag, 315-323.
45. Hayball, P. J., and Meffin, P. J. (1987). Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. III. Fenoprofen disposition. J. Pharmacol. Exp. Ther., 240, 631-636.
46. Hayball, P. J., Nation, R. L., Bochner, F., Newton, J. L., and Massy-Westropp, R. A. (1991). Plasma protein binding of ketoprofen enantiomers in man: Method development and its application. Chirality, 3, 460-466.
47. Hayball, P. J., Nation, R. L., and Bochner, F. (1992). Stereoselective interactions of ketoprofen glucuronides with human plasma protein and serum albumin. Biochem. Pharmacol., 44, 291-299.
48. Hayball, P. J., Nation, R. L., Bochner, F., Sansom, L. N., Ahern, M. J., and Smith, M. D. (1991). The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis. Br. J. Clin. Pharm., 31, 546-550.
49. Hayball, P. J., Wrobel, J., Tamblyn, J. G., and Nation, R. L. (1994). The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the racemate. Br. J. Clin. Pharm., 37, 75-78.
50. Hermening, A., Gräfe, A. K., Mayer, S., Mutschler, E., and Spahn-Langguth, H. (1995). Pharmacokinetics of fibrates and their acyl glucuronides: Inclusion of a reversible metabolic step and covalent binding into kinetic modelling. Naunyn Schmiedeberg's Arch. Pharmacol., 351 (suppl), R5.
51. Hutt, A. J., Caldwell, J., and Fournel-Gigleux, S. (1988). The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences. Biochem. Pharmacol., 37, 105-114.
52. Iwakawa, S., Spahn, H., Benet, L. Z., and Lin, E. T. (1988). Carprofen glucuronides: Stereoselective degradation and interaction with human serum albumin. Pharm. Res., 5 (suppl.), S214.
53. Iwakawa, S., Suganuma, T., Lee, S. F., Spahn, H., Benet, L. Z., and Lin, E. T. (1989). Direct determination of diastereomeric carprofen glucuronides in human plasma and urine and preliminary measurements of stereoselective metabolic and renal elimination after oral administration of carprofen in man. Drug, Metab. Disp., 17, 474-480.
54. Iwakawa, S., Spahn, H., Benet, L. Z., and Lin, E. T. (1990). Stereoselective binding of the glucuronide conjugates of carprofen enantiomers to human serum proteins. Biochem. Pharmacol., 39, 949-953.
55. Iwakawa, S., Spahn, H., Benet, L. Z., and Lin, E. T. (1991). Stereoselective disposition of carprofen, flunoxaprofen, and naproxen in rats. Drug Metab. Disp., 19, 853-857.
56. Iwakawa, S., Spahn-Langguth, H., Benet, L. Z., and Lin, E. T. (1997). Carprofen acyl glucuronides: Stereoselective degradation and interaction with human serum proteins (submitted for publication.)
57. Iwaki, M., Bischer, A. C., Nguyen, A. C., McDonagh, A. F., and Benet, L. Z. (1995). Stereoselective disposition of naproxen glucuronide in the rat. Drug Metab. Disp. (in press).
58. Jones, M. E., Sallustio, B. C., Purdie, Y. J., and Meffin. P. J. (1986). Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid protein binding. J. Pharmacol. Exp. Ther., 238, 288-294.
59. King, A. R., and Dickinson, R. G. (1993). Studies on the reactivity of acyl glucuronides. IV. Covalent binding of diflunisal to tissues of the rat. Biochem. Pharmacol., 45, 1043-1047.
60. Klaasen, C. D., and Watkins, J. B. (1984). Mechanisms of bile formation, hepatic uptake and biliary excretion. Pharmacol. Rev., 36, 1-67.
61. Knadler, M. P., and Hall, S. D. (1991). Stereoselective hydrolysis of flurbiprofen conjugates. Drug Metab. Disp., 19, 280-282.
62. Knadler, M. P., Brater, D. C., and Hall, S. D. (1992). Stereoselective disposition of flurbiprofen in uraemic patients. Br. J. Clin. Pharm., 33, 377-383
63. Kretz-Rommel, A. and Boelsterli, U. A. (1994). Selective protein adducts to membrane proteins in cultured rat hepatocytes exposed to diclofenac: Radiochemical and immunochemical analysis. Mol. Pharmacol., 45, 237-244.
64. Kroemer, H. K., and Klotz, U. (1992). Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet., 23, 292-310.
65. Langguth, P. (1994). Compartmental approaches and integral input parameters. Ist International Workshop on Strategies for Oral Drug Delivery, Uppsala, Sept. 1994.
66. Langguth, P., Lee, K. M., Spahn-Langguth, H., and Amidon, G. L. (1994). Variable gastric emptying and discontinuities in drug absorption profiles: Dependence of rates and extent of cimetidine absorption on motility phase and pH. Biopharm. Drug Disp., 15, 719-746.
67. Magdalou, J., Chajes. V., Lafaurie, C., and Siest, G. (1990). Glucuronidation of 2-arylpropionic acids pirprofen, flurbiprofen, and ibuprofen by liver microsomes. Drug Metab. Disp., 18, 692-697.
68. Mayer, S. (1992). Analytik und Pharmakokinetik des chiralen Lipidsenkers Beclobrat. Ph.D. Thesis, Department of Pharmacology, Johann Wolfgang Goethe-University Frankfurt/M.
69. Mayer, S., Spahn-Langguth, H., Gikalov, I., and Mutschler, E. (1993a). Pharmacokinetics of beclobric acid enantiomers and their glucuronides after single and multiple p.o. dosage of rac-beclobrate. Arzneim-Forsch./Drug Res., 42-2, 1354-1358.
70. Mayer, S., Mutschler, E., Benet, L. Z., and Spahn-Langguth, H. (1993b). In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers. Chirality, 5, 120-125.
71. McKinnon, G. E., and Dickinson, R. G. (1989). Covalent binding of diflunisal and probenecid to plasma protein in humans: Persistence of the adducts in the circulation. Res. Commun. Chem. Pathol. Pharmacol., 66, 339-354.
72. Meffin, P. J., Sallustio, B. C., Purdie, Y. J., and Jones, M. E. (1986). Enantioselective disposition of 2-arylpropionic acid nonsteroidal antiinflammatory drugs: I. 2. Phenylpropionic acid disposition. J. Pharmacol. Exp. Ther., 238, 280-287.
73. Midha, K. K., Roscoe, R. M. H., Wilson, T. W., and Cooper, J. K. (1983). Pharmacokinetics of glucuronidation of propranolol following oral administration in humans. Biopharm. Drug Disp., 4, 331-338.
74. Nakamura, Y., and Yamaguchi, T. (1987). Stereoselective metabolism of 2-phenylpropionic acid in rats: I. In vitro studies on the stereselective isomerization and glucuronidation of 2-phenylpropionic acid. Drug Metab. Disp., 15, 529-534.
75. Ojingwa, J., Spahn-Langguth, H., and Benet, L. Z. (1994). Reversible binding of tolmetin, zomepirac and their glucuronide conjugates to human serum albumin. J Pharmacokin. Biopharm., 22, 19-40.
76. Ojingwa, J., Spahn-Langguth, H., and Benet, L. Z. (1994). Irreversible binding of tolmetin to macromolecules via its glucuronide: Binding to blood constituents, tissue homogenates and subcellular fractions in vitro. Xenobiotica, 24, 495-506.
77. Ott, R. J., Giacomini, K. M. (1993). Stereoselective transport of drugs across epithelia. In: I. W. Wainer, (ed). Drug Stereochemistry: Analytical Methods and Pharmacology, New York: Marcel Dekker, 281-314.
78. 171Er-labeled sustained release tablets. Pharm. Res., 4, 486-491.
79. Pedrazzini, S., De Angelis, M., Zanoboni Muciaccia, Z., Sacchi, C., and Forgione, A. (1988). Stereochemical pharmacokinetics of the 2-arylpropionic acid non-steroidal antiinflammatory drug flunoxaprofen in rats and man. Arzneim-Forsch./Drug Res., 38, 1170-1175.
80. Rowe, B. J., and Meffin, P. J. (1984). Diisopropylfluorophosphate increases clofibric acid clearance: Supporting evidence for a futile cycle. J. Pharmacol. Exp. Ther., 230, 237-241.
81. Runkel, R., Mroszczak, E., Chaplin, M., Sevelius, H., and Segre, E. (1978). Naproxen-probenecid interaction. Clin. Pharmacol. Ther., 24, 706-713.
82. Sallustio, B. C., Knights, K, M., Roberts, B. J., and Zacest, R. (1991). In vivo covalent binding of clofibric acid to human plasma proteins and rat liver proteins. Biochem. Pharmacol., 42, 1421-1425.
83. Segre, G., Bianchi, E., and Zanolo, G. (1988). Pharmacokinetics of flunoxaprofen in rats, dogs, and monkeys. J. Pharm. Sci., 77, 670-673.
84. Simmonds, R. G., Woodage, T. J., Duff, S. M., and Green, J. N. (1980). Stereospecific inversion of R-(-)-benoxaprofen in rat and man. Eur. J. Drug Metab. Pharmacokinet., 5, 169-172.
85. Smith, P. C., and Benet, L. Z. (1986). Characterization of the isomeric esters of zomepirac glucuronide by proton NMR. Drug Metab. Disp., 14, 503-505.
86. Smith, P. C., Langendiijk, P. N. J., Hasegawa, J., and Benet, L. Z. (1985). Effect of probenecid on the formation and elimination of acyl glucuronides: Studies with zomepirac. Clin. Pharmacol. Ther., 38, 121-127.
87. Smith, P. C., McDonagh, A. F., and Benet, L. Z. (1986). Irreversible binding of zomepirac to plasma protein in vitro and in vivo. J. Clin. Invest., 77, 934-939.
88. Smith, P. C., Benet, L. Z., and McDonagh, A. F. (19890a). Covalent binding of zomepirac glucuronide to proteins: Evidence for a Schiff base mechanism. Drug Metab. Disp., 18, 639-644.
89. Smith, P. C., McDonagh, A. F., and Benet, L. Z. (1990b). Effect of an esterase inhibitor on the disposition of zomepirac and its covalent binding to plasma proteins in the guinea pig. J. Pharmacol. Exp. Ther., 230, 218-224.
90. Smith, P. C., Song, W. Q., and Rodriguez, R. J. (1992). Covalent binding of etodolac acyl glucuronide to albumin In vitro. Drug. Metab. Disp., 20, 962-965.
91. Spahn, H. (1988). Assay method for the product formation in in vitro enzyme kinetic studies of uridine diphosphoglucuronosyltransferases: 2-Arylpropionic acids. J. Chromatogr., 430, 368-375.
92. Spahn, H. (1989). Characterization of stereoselective processes in drug metabolism and pharmacokinetics. Habilitation Thesis, Department of Pharmacology, Johann Wolfgang Goethe-University, Frankfurt/M.
93. Spahn, H, and Benet, L. Z. (1987a). Influence of probenecid on the glucuronidation of naproxen enantiomers by hepatic UDP-glucuronosyltransferases in rat liver microsomes. Pharm. Res., 4 (suppl.), S111l.
94. Spahn, H., and Benet, L. Z. (1987b). Enantioselectivity of hepatic UDP-glucuronyl-transerases in rat liver microsomes towards 2-arylpropionic acids: Glucuronidation of naproxen enantiomers. In J. M. Aiache, J. Hirtz (eds.), 3rd European Congress of Biopharmaceutics and Pharmacokinetics Proceedings, Vol II, Experimental Pharmacokinetics, Freiburg 1987, 261-268.
95. Spahn, H., Hale, V., Iwakawa, S., and Benet, L. Z. (1989c). Effects of probenecid on the hepatic elimination of flunoxaprofen. Naunyn Schmiedeberg's Arch. Pharmacol. (suppl.), 14.
96. Spahn, H., Iwakawa, S., Lin, E. T., and Benet, L. Z. (1989a): Procedures to properly characterize in vivo and the in vitro enantioselective glucuronidation: studies with benoxaprofen glucuronides. Pharm. Res., 6, 125-132.
97. Spahn, H., Iwakawa, S., Lin, E. T., and Benet, L. Z. (1987). Influence of probenecid on the urinary excretion rates of the diastereomeric benoxaprofen glucuronides. Eur. J. Drug Metab. Pharmacokinet., 12, 233-239.
98. Spahn, H., Iwakawa, S., and Benet, L. Z. (1988). Stereoselective formation and degradation of flunoxaprofen glucuronides in microsomal incubations. Pharm. Res., 5 (suppl.), S200.
99. Spahn, H., Iwakawa, S., Ojingwa, J., and Benet, L. Z. (1988b). Glucuronidation of flunoxaprofen enantiomers by UDPGTs from different sources. International Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem, May/June 1988.
100. Spahn, H., Spahn, L. Pflugmann, G., Mutschler, E., and Benet, L. Z. (1988c). Measurement of carprofen enantiomers in human plasma and urine using L-leucinamide as chiral coupling component. J. Chromatogr., 433, 331-338.
101. Spahn, H., Spahn, I., and Benet, L. Z. (1989b). Probenecid-induced changes in the clearance of carprofen enantiomers - a preliminary study. Clin. Pharmacol. Ther., 45, 500-505.
102. Spahn, H., Zia-Amirhosseini, P., Näthke, L. Mohri, K., and Benet, L. Z. (1990). Characterization of drug adducts formed with proteins via acyl glucuronides - by electrophoresis and blotting.. Pharm. Res., 7 (suppl.), S257.
103. Spahn-Langguth, H. (1992). The use of mean residence time concepts to define precursor-product relationships in drug delivery and metabolism. 2nd Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem, May 1992.
104. Spahn-Langguth, H., and Benet, L. Z. (1992a): Active and reactive phase-II metabolities: The glucuronides pathway. In Crommelin, D. J. A., Midha, K. K. (eds.) Topics in Pharmaceutical Sciences 1991, Proc. Intl. Congress of Pharmaceutical Sciences, Washington DC. Medpharm Scientific Publishers, Stuttgart, pp. 505-516.
105. Spahn-Langguth, H., and Benet, L. Z. (1992). Acyl glucuronides revisited: Is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab. Rev., 24, 5-48.
106. Spahn-Langguth, H., and Benet, L. Z. (1993). Microsomal acyl glucuronidation: Enzyme kinetic studies with labile glucuronides. Pharmacology, 46, 268-273.
107. Spahn-Langguth, H., Zia-Amirhosseini, P., Iwakawa, S., Ojingwa, J., Büschges R., and Benet, L. Z. (1994a). Aktive und reaktive Glucuronide: Reversible und irreversible Interaktionen mit Proteinen. In, H. J. Dengler, and E. Mutschler (eds.) Fremdstoffmetabolismus und Klinische Pharmakologie, Stuttgart: Gustav Fischer Verlag, pp. 29-50.
108. Spahn-Langguth, H., Gräfe, A. K. , Mayer, S., and Büschges, R. (1994b). Fibrates: The occurrence of active and reactive metabolites. In, Reid, E., Hill, H. M., and Wilson, I. D. (eds.), Biofluid and Tissue Analysis for Drugs Including Hyperlipidaemics, Methodological Surveys in Bioanalysis of Drugs, Vol. 23, Cambridge. The Royal Society of Chemistry, 87-102.
109. Spahn-Langguth, H., Benet, L. Z., Möhrke, W., and Langguth, P. (1996). First-pass phenomena: Sources of stereoselectivities and variabilities of concentration-time profiles after oral dosage.
110. Stafanger, G., Larsen, H. W., Hansen, H., and Sorensen, K. (1981). Scand. J. Rheumatol., 10, 189-192.
111. Stogniew, M., and Fenselau, C. (1982). Electrophilic reactions of acyl-linked glucuronides: Formation of clofibrate mercapturate in humans. Drug Metab. Disp., 10, 609-613.
112. Strolin-Benedetti, M., Frigerio, E., Tamassia, V., Noseda G., and Caldwell J. (1992). The dispositional enantioselectivity of indobufen in man. Biochem. Pharmacol., 43, 2032-2034.
113. Taylor, I. W., Chasseaud, L. F., Taylor, T., James, I., Dorf, G., and Darragh, A. (1991). Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy young and elderly subjects: Comparison with elderly rheumatic patients. Br. J. Clin. Pharmac., 32, 242-245.
114. Taki, Y., Sakane, T., Nadai, T., Sezaki, H., Langguth, P., and Yamashita, S. (1995). Gastrointestinal absorption of peptide drugs: Quantitative evaluation of the degradation and permeation of metkephamid in rat small intestine. J. Pharmacol. Exp. Ther. J. Pharmacol. Exp. Ther., 274, 373-377.
115. Upton, R. A., Williams, R. L., Buskin, J. N., and Jones, R. M. (1982). Effects of probenecid on ketoprofen kinetics. Clin. Pharmacol. Ther., 31, 705-712.
116. Upton, R. A., Williams, R. L., Kelly, J., and Jones, R. M. (1984). Br. J. Clin. Pharmac., 18, 207-214.
117. 14C]-fenofibrate in laboratory animals and humans. Chirality, 1, 197-201.
118. Wells, D. S., Janssen, F. W., and Ruelius, H. W. (1987). Interactions between oxaprozin glucuronide and human serum albumin. Xenobiotica, 17, 1437-1449.
119. Williams, A.M., and Dickinson, R. G. (1994). Studies on the reactivity of acyl glucuronides-VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro. Biochem. Pharmacol., 47, 457-467.
120. Williams. A. M., Worrall, S., DeJersey, J., and Dickinson, R. G. (1992). Studies on the reactivity of acyl glucuronides: Glucuronide-derived adducts of valproic acid and plasma proteins and anti-adduct antibodies in humans. Biochem. Pharmacol., 43, 745-755.
121. Williams, A. M. Worralls, S., De Jersey, J., and Dickinson R. G. (1995). Studies on the reactivity of acyl glucuronides-VIII. Generation of an antiserum for the detection of diflunisal-modified proteins in diflunisal dosed rats. Biochem. Pharmacol., 49, 209-217.
122. van Breemen, R. B., and Fenselau, C. (1985). "Acylation of albumin by 1-O-acyl glucuronides. Drug Metab. Disp., 13, 318-320.
123. Van der Ouweland, F. A., Jansen, P. A. F., Tan, Y., Van de Putte, L. B. A., Van Ginneken, C. A. M., and Gribnau, F. W. J. (1988). Pharmacokinetics of high dosage naproxen in elderly patients. Int. J. Clin. Pharmacol. Ther. Toxicol., 26, 143-147.
124. Voith, B., Spahn-Langguth, H., Paliege, R., Knauf, H., and Mutschler, E. (1993). Etacrynic acid: Evaluation of the kinetics/effect relationship. Arch. Pharm. (Weinheim), 326, 629 (abstract).
125. Volland, C., and Benet, L. Z. (1991). In vitro enantioselective glucuronidation of fenoprofen. Pharmacology, 43, 53-60.
126. Volland, C., Sun, H., Dammeyer, J., and Benet, L. Z. (1991). Stereoselective degradation of the fenoprofen acyl glucuronide enantiomers and irreversible binding to plasma proteins. Drug. Metab. Disp., 19, 1080-1086.
127. Vree, T. B., Hekster, Y. A., and Anderson, P. G. (1992). Contribution of the human kidney to the metabolic clearance of drugs. Ann. Pharmacother., 26, 1421-1428.
128. Yamaguchi, T., and Nakamura, Y. (1987). Stereoselective metabolism of 2-phenylpropionic acid in rat. II. Studies on the organs responsible for the optical isomerization of 2-phenylpropionic acid in rat in vivo. Drug Metab. Disp., 15, 535-539.
129. Zakim, D., and Vessey, D. A. (1973): Techniques for the characterization of UDP-glucusonyl transferase, glucose-6-phosphatase, and other tightly bound microsomal enzymes. Methods Biochem. Anal., 21, 1-37.
130. Zia-Amirhosseini, P. (1994). Hypersensitivity to nonsteroidal anti-inflammatory drugs: Exploration of a theory. Ph.D. Thesis, School of Pharmacy, University of California, San Francisco.
131. Zia-Amirhosseini, P., Spahn, H., and Benet, L. Z. (1988). Measurement of naproxen, desmethylnaproxen and their conjugates in plasma and urine. Pharm. Res., 5, (suppl.), S-200.
132. Zia-Amirhosseini, P., Ojingwa, J., Spahn-Langguth, H., McDonagh, A. F., and Benet, L. Z. (1994). Enhanced covalent binding of tolmetin to proteins in humans after multiple dosing. Clin. Pharmacol. Ther., 55, 21-27.
133. Zia-Amirhosseini, P., Harris, R. Z., Brodsky, F. M., Benet, L. Z. (1995). Hypersensitivity to nonsteroidal antiinflammatory drugs. Nature Med., 1, 2-4.