Role of p-glycoprotein and cytochrome p450 3a in limiting oral absorption of peptides and peptidomimeticst

Journal of Pharmaceutical Sciences

Volumn 87, Issue 11, 1998, Pages 1322-1330

  Wacher, Vincent J ^a  

^a AvMax Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLCHICINE; CYCLOSPORIN; CYCLOSPORIN A; CYTOCHROME P450; DOXORUBICIN; IMMUNOSUPPRESSIVE AGENT; KETOCONAZOLE; MIDAZOLAM; MORPHOLINE DERIVATIVE; PROTEINASE INHIBITOR; RHODAMINE; RIFAMPICIN; RITONAVIR; SAQUINAVIR; VALSPODAR; VERAPAMIL; VINBLASTINE;

AREA UNDER THE CURVE; CHROMOSOME 7Q; CLINICAL TRIAL; CONFERENCE PAPER; DRUG ABSORPTION; DRUG BIOAVAILABILITY; ENZYME SPECIFICITY; HUMAN; HUMAN CELL; HUMAN TISSUE; INTESTINE CELL; ORAL DRUG ADMINISTRATION; PHASE 1 CLINICAL TRIAL; PROTEIN BINDING; PROTEIN EXPRESSION;

EID: 0031765907     PISSN: 00223549     EISSN: None     Source Type: Journal    
DOI: 10.1021/js980082d     Document Type: Article

References (83)

1. Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F. P. Intel-individual 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. 1994, 270, 414-423.
2. Watkins, P. B.; Wrighton, S. A.; Schuetz, E. G.; Molowa, D. T.; Guzelian, P. S. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J. Clin. Invest. 1987, 80, 1029-36.
3. Wacher, V. J.; Wu, C.-Y.; Benet, L. Z. Overlapping substrate specificities and tissue distribution of cytocnrome P450 3A and P-glycoprotein: implications for drug delivery and cancer chemotherapy. Mol. Carcinog. 1995, 13, 129-34.
4. Wacher, y. J.; Salphati, L.; Benet, L. Z. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Delivery Rev. 1996, 20, 99-112.
5. Benet, L. Z.; Kroetz, D. L.; Sheiner, L. B. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In Goodman and Oilman's The Pharmacologie Basis of Therapeutics, 9th ed.; Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W., Goodman, A. G., Eds.; McGraw-Hill; New York, 1996; pp 3-27.
6. Parkinson, A. An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials. Toxicol. Pathol. 1996, 24, 45-57.
7. 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.; Nebert, D. W. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996, 6, 1-42.
8. Gonzalez, F. J.; Schmid, B. J.; Umeno, M.; McBride. O. W.; Hardwick, J. P.; Meyer, U. A.; Gelboin, H. V.; Idle, J. R. Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA 1988, 7, 79-86.
9. Hashimoto, H.; Toide, K.; Kitamura, R.; Fujita, M.; Tagawa, S.; Itoh, S.; Kamataki, T. Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur. J. Biochem. 1993,218, 585595.
10. Aoyama, T.; Yamano, S.; Waxman, D. J.; Lapenson, D. P.; Meyer, U. A.; Fischer, V.; Tyndale, R.; Inaba, T.; Kalow, W.; Gelboin, H. V.; Gonzalez, F. J. Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNAexpressed hPCNl and hPCN3 for the metabolism of steroid hormones and cyclosporine. J. Biol. Chem. 1989,264,1038895.
11. Schuetz, J. D.; Molowa, D. T.; Guzelian, P. S. Characterization of a cDNA encoding a new member of the glucocorticoidresponsive cytochromes P450 in human liver. Arch. Biochem. Biophys. 1989, 274, 355-65.
12. Wrighton S. A.; Ring, B. J.; Watkins; P. B., VandenBranden M. Identification of a polymorphically expressed member of the human cytochrome P-450III family. Mol. Pharmacol. 1989, 36, 97-105.
13. Wrighton S. A.; Brian, W. R.; Sari, M.-A.; Iwasaki, M.; Guengerich, F. P.; Raucy, J. L.; Molowa, D. T.; VandenBranden, M. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol. Pharmacol. 1990, 38, 207-213.
14. Kitada, M.; Kamataki, T.; Itahashi, K.; Rikihisa, T.; Kato, R.; Kanakubo, Y. Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Arch. Biochem. Biophys. 1985, 241, 275-280.
15. Wrighton, S. A.; VandenBranden, M. Isolation and characterization of human fetal liver cytochrome P450HLp2: a third member of the P450III gene family. Arch. Biochem. Biophys. 1989,26, 144-151.
16. Komori, M.; Nishio, K; Ohi, H.; Kitada, M.; Kamataki, T. Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450. J. Biochem. 1989, 105, 161-163.
17. Komori, M.; Nishio, K; Kitada, M.; Shiramatsu, K.; Muroya, K; Soma, M.; Nagashima, K.; Kamataki, T. Fetus-specific expression of a form of cytochrome P-450 in human livers. Biochemistry 1990, 29, 4430-3.
18. Schuetz, J. D.; Beach, D. L.; Guzelian, P. S. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 1994, 4, 11-20.
19. Hakkola, J.; Fasanen, M.; Purkunen, R.; Saarikoski, S.; Pelkonen, p.; Maenpaa, J.; Rane, A.; Raunjo, H. Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochem. Pharmacol. 1994,48, 59-64.
20. Watkins, P. B.; Wrighton, S. A.; Maurel, P.; Schuetz, E. G.; Mendez-Picon, G.; Parker, G. A.; Guzelian, P. S. Identification of an inducible form of cytochrome P-450 in human liver. Proc. Natl. Acad. Sei. U.S.A. 1985, 82, 6310-6314.
21. Molowa, D. T.; Schuetz, E. G.; Wrighton, S. A.; Watkins, P. B.; Kremers, P.; Mendez-Picon, G.; Parker, G. A.; Guzelian, P. S. Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc. Natl. Acad. Sei. U.S.A. 1986, 83, 5311-5315.
22. Hashimoto, H.; Nakagawa, T.; Yokoi, T.; Sawada, M.; Itoh, S.; Kamataki, T. Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins. Cancer Res. 1995, 55, 787-791.
23. Cresteil, T.; Beaune, P.; Kremers, P.; Flinois, J.-P.; Leroux, J.-P. Drug metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P450. Pediatr. Pharmacol. 1982, 2, 199-207.
24. Waxman, D. J.; Lapenson, D. P.; Aoyama, T.; Gelboin, H. V.; Gonzalez, F. J.; Korzekwa, K. Steroid hormone hydroxylase specificities of eleven cDNA-expressed cytochrome P450s. Arch. Biochem. Biophys. 1991, 290, 160-166.
25. Kitada, M.; Kamataki, T.; Itahashi, K.; Rikihisa, T.; Kanakubo, Y. Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations. Biochem. Pharmacol. 1987, 36, 453-456.
26. Gorski, J. C.; Hall, S. D.; Jones, D. R.; VandenBranden, M.; Wrighton, S. A. Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem. Pharmacol. 1994, 47, 16431653.
27. Kolars, J. C.; Schmiedlin-Ren, P.; Schuetz, J. D.; Fang, C.; Watkins, P. B. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 1992,90, 1871-1878.
28. Schuetz, E. G.; Schuetz, J. D.; Strom, S. C.; Thompson, M. T.; Fisher R. A.; Molowa, D. T.; Li, D.; Guzelian, P. S. Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology 1993, 18, 1254-62.
29. Kocarek, T. A.; Schuetz, E. G.; Strom, S. C.; Fisher, R. A.; Guzelian, P. S. Comparative analysis of cytochrome P450 3A induction in primary cultures of rat, rabbit and human hepatocytes. Drug Metab. Dispos. 1995, 23, 415-421.
30. Greuet, J.; Pichard, L.; Bonfils, C.; Domergue, J.; Maurel, P. The fetal specific gene CYP3A7 is inducible by rifampicin in adult human hepatocytes in primary culture. Biochem. Biophys. Res. Commun. 1996, 225, 689-694.
31. Schuetz, E. G.; Beck, W. T.; Schuetz, J. D. Modulators and substrates of P-glycoprotein and cytochrome P450 3A coordinately upregulate these proteins in human colon carcinomas. Mol. Pharmacol. 1996, 49: 311-318.
32. Thummel, K. E.; Shen, D. D.; Podoll, T. D.; Kunze, K. L.; Trager WF.; Hartwell, P. S.; Raisys, V. A.; Marsh, C. L.; McVicar, J. P.; Barr, D. M.; Perkins, J. D.; Carithers, R. L., Jr. Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. J. Pharmacol. Exp. Ther. 1994, 277, 549-556.
33. Thummel, K. E.; Shen, D. D.; Podoll, T. D.; Kunze, K. L.; Trager W. F.; Bacchi, C. E.; Marsh, C. L.; McVicar, J. P.; Barr, D. M.; Perkins, J. D.; Carithers, R. L., Jr. Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J. Pharmacol. Exp. Ther. 1994, 277, 557-566.
34. Kolars, J. C.; Lown, K. S.; Schmiedlin-Ren, P.; Ghosh, M.; Fang, C.; Wrighton, S. A.; Merion, R. M.; Watkins, P. B. CYP3A gene expression in human gut epithelium. Pharmacogenetics 1994, 4, 247-59.
35. Lown, K. S.; Kolars, J. C.; Thummel, K. E.; Barnett, J. L.; Kunze, K. L.; Wrighton, S. A.; Watkins, P. B. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab. Dispos. 1994, 22, 947-55.
36. McKinnon, R. A.; Burgess, W. M.; Hall, P. de la M.; RobertsThomson, S. J.; Gonzalez, F. J.; McManus, M. E. 1995. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut 1995, 36, 259-267.
37. Kivistö, K. T.; Bookjans, G.; Fromm, M. F.; Griese, E.-U.; Münzel, P.; Kroemer, H. K. Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. Br, J. Clin. Pharmacol. 1996, 42, 387-389.
38. Lown, K. S.; Bailey, D. G.; Fontana, R. J.; Janardan, S. K.; Adair, C. H.; Fortlage, L. A.; Brown, M. B.; Guo, W.; Watkins, P. B. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J. Clin. Invest. 1997, 99, 2545-2553.
39. Lown, K. S.; Mayo, R. R.; Leichtman, A. B.; Hsiao, H. L.; Turgeon, D. K; Schmiedlin-Ren, P.; Rossi, S. J.; Brown, M. B.; Guo, W.; Benet, L. Z.; Watkins, P. B. Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavailability ofcyclosporin A. Clin. Pharmacol. Ther. 1997, 62, 248-260.
40. Paine, M. F.; Khalighi, M.; Fisher, J. M.; Shen, D. D.; Kunze, K. L.; Marsh, C. L.; Perkins, J. D. Thummel K. E. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J. Pharmacol. Exp. Ther. 1997, 283, 1552-1562.
41. Schmiedlin-Ren, P.; Thummel, K. E.; Fisher, J. M.; Paine, M. F.; Lown, K. S.; Watkins, P. B. Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of la,25dihydroxyvitamin Ds. Mol. Pharmacol. 1997, 51, 741-54.
42. De Waziers, I.; Cugnenc, P. H.; Yang, C. S.; Leroux, J.-P.; Beaune, P. H. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J. Pharmacol. Exp. Ther. 1990,253, 387-394.
43. Paine, M. F.; Shen, D. D.; Kunze, K. L.; Perkins, J. D.; Marsh, C. L.; McVicar, J. P.; Barr, D. M.; Gillies, B. S.; Thummel, K. E. First-pass metabolism of midazolam by the human intestine. Clin. Pharmacol. Ther. 1996, 60, 14-24.
44. Thummel, K. E.; O'Shea, D.; Paine, M. F.; Shen, D. D.; Kunze, K. L.; Perkins, J. D.; Wilkinson, G. R. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYPSA-mediated metabolism. Clin. Pharmacol. Ther. 1996, 59, 491-502.
45. Lampen, A.; Christians, U.; Bader, A.; Hackbarth, I.; Sewing, K.-F. Drug interactions and interindividual variability of ciclosporin metabolism in the small intestine. Pharmacology 1996,52, 159-168.
46. Janardan, S. K.; Lown, K. S.; Schmiedlin-Ren, P.; Thummel, K. E.; Watkins, P. B. Selective expression of CYP3A5 and not CYP3A4 in human blood. Pharmacogenetics 1996, 6, 379-385.
47. Jounaïdi, Y.; Hyrailles, V.; Gervot, L.; Maurel, P. Detection of a CYP3A5 allelic variant: a candidate for the polymorphic expression of the protein? Biochem. Biophys. Res. Commun. 1996, 221, 466-470.
48. Schuetz, E. G.; Schuetz, J. D.; Grogan, W. M.; Naray-FejesToth, A.; Fejes-Toth, G.; Raucy, J.; Guzelian, P.; Gionela, K.; Watlington, C. O. Expression of cytochrome P450 3A in amphibian, rat and human kidney. Arch. Biochem. Biophys. 1992, 294, 206-214.
49. Haehner, B. D.; Gorski, J. C.; VandenBranden, M.; Wrighton, S. A.; Janardan, S. K.; Watkins, P. B.; Hall, S. D. Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol. Pharmacol. 1996, 50, 52-59.
50. Wheeler, C. W.; Wrighton, S. A.; Guenthner, T. M. Detection of human lung cytochromes P450 that are immunochemically related to cytochrome P450IIE1 and cytochrome P450IIIA. Biochem. Pharmacol. 1992, 44, 183-186.
51. Anttila, S.; Hukkanen, J.; Hakkola, J.; Stjernvall, T.; Beaune, P.; Edwards, R. J.; Boobis, A. R.; Pelkonen, O.; Raunio, H. Expression and localization of CYP3A4 and CYP3A5 in human lung. Am. J. Respir. Cell Mol. Biol. 1997, 16, 242249.
52. Murray GI, Pritchard S, Melvin WT, Burke MD. Cytochrome P450 CYP3A5 in the human anterior pituitary gland. FEBS Lett. 1995, 364, 79-82.
53. Lown, K. S.; Ghosh, M.; Watkins, P. B.. Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab. Dispos. 1998, 26, 185-187.
54. Endicott, J. A.; Ling, V. The biochemistry of P-glycoprotein mediated multidrug resistance. Anna. Rev. Biochem. 1989, 58, 137-171.
55. Borst, P.; Schinkel, A. H.; Smit, J. J. M.; Wagenaar, E.; Van Deemter, L.; Smith, A. J.; Eijdems, E. W. H. M.; Baas, F.; Zaman, G. J. R. Classical and novel forms of multidrug resistance and the physiological functions of P-glycoprotein in mammals. Pharmacol. Ther. 1993, 60, 289-299.
56. Gottesman, I. I.; Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 1993, 62, 385-427.
57. Muller, M.; Roelofson, H.; Jansen, P. L. M. Secretion of organic anions by hepatocytes: involvement of homologues of the multidrug resistance protein. Semin. Liv. Disease 1996, 16, 211-220.
58. Fojo, A. T.; Ueda, K.; Slamon, D. J.; Poplack, D. G.; Gottesman, M. M.; Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sei. U.S.A. 1987, 84, 265-269.
59. Thiebaut, F.; Tsuruo, T.; Hamada, H.; Gottesman, M. M.; Pastan, L; Willingham, M. C. Cellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sei. U.S.A. 1987,84, 77357738.
60. Murray, G. L; Barnes, T. S.; Sewell, H. F.; Ewen, S. W. B.; Melvin, W. T.; Burke, M. D. The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br. J. Clin. Pharmacol. 1988, 25, 465-475.
61. Fitzsimmons, M. E.; Collins, J. M. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P450 3A4. Potential contribution to high first-pass metabolism. Drug Metab. Dispos. 1997, 25, 256-266.
62. Tateishi, T.; Soucek, P.; Caraco, Y.; Guengerich, F. P.; Wood, A. J. J. Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem. Pharmacol. 1997,53, 111-116.
63. Schuetz, E. G.; Schinkel, A. H.; Helling, M. V.; Schuetz, J. D. P-glycoprotein, a major determinant of rifampicin-inducible expression of cytochrome P450 3A in mice and humans. Proc. Natl. Acad. Sei. U.S.A. 1996, 93, 4001-4005.
64. Wu, C.-Y.; Benet, L. Z.; Hebert, M. F.; Gupta, S. K; Rowland, M.; Gomez, D. Y.; Wacher, V. J. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine. Clin. Pharmacol. Ther. 1995, 58, 492-497.
65. Hebert, M. F.; Roberts, J. P.; Prueksaritanont, T.; Benet, L. Z. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin. Pharmacol. Ther. 1995, 55, 15-19.
66. Gomez, D. Y.; Wacher, V. J.; Tomlanovich, S. J.; Hebert, M. F.; Benet, L. Z. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin. Pharmacol. Ther. 1995, 58, 15-19.
67. Ducharme M. P.; Warbasse, L. H.; Edwards, D. J. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin. Pharmacol. Ther. 1995,57, 485491.
68. Chang, T.; Benet, L. Z.; Hebert, M. F. The effect of watersoluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers. Clin. Pharmacol. Ther. 1996, 59, 297303.
69. Kplars, J. C.; Awni, W. M.; Merion, R. M.; Watkins, P. B. First-pass metabolism of cyclosporine by the gut. Lancet 1991,338, 1488-1490.
70. Flicker, G.; Drewe, J.; Huwyler, J.; Gutmann, H.; Beglinger, C. Relevance of P-glycoprotein for the enterai absorption of cyclosporin A, in vitro-in vivo correlation. Br. J. Pharmacol. 1996, 118, 1841-1847.
71. Schinkel, A. H.; Wagenaar, E.; van Deemter, L.; Mol, C. A. A. M.; Borst, P. Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin and cyclosporin A. J. Clin. Invest. 1995, 96, 1698-1705.
72. Merry, C.; Mulcahy, F.; Barry, M.; Gibbons, S.; Back, D. Saquinavir interaction with midaEolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. AIDS 1997, 11, 268-269.
73. Kempf, D. J.; Marsh, K. C.; Kumar, G.; Rodrigues, A. D.; Denissen, J. F.; McDonald, E.; Kukulka, M. J.; Hsu, A.; Granneman, G. R.; Baroldi, P. A.; Sun, E.; Pizzuti, D.; Plattner, J. J.; Norbeck, D. W.; Leonard, J. M. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by administration with ritonavir. Antimicrob. Agents Chemother. 1997, 41, 654-660.
74. Merry, C.; Barry, M. G.; Mulcahy, F.; Ryan, M.; Heavey, J.; Tjia, J. F.; Gibbons, S. E.; Breckenridge, A. M.; Back, D. J. Saquinavir pharmacokinetics alone and in combination with ritonavir in HlV-infected patients. AIDS 1997,11, F29-F33.
75. James, J. S. Grapefruit juice and saquinavir. Aids Treatment News 1995, 235, 5-6.
76. Kirn, A. E.; Dintaman, J. M.; Waddell, D. S.; Silverman, J. A. Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. J. Pharmacol. Exp. Ther. 1998, in press.
77. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 66, 55-63.
78. Hansen, M. B.; Nielsen, S. E.; Berg, K. Reexamination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods 1989, 119, 203-210.
79. Hunter, J.; Hirst, B. H.; Simmons, N. L. Epithelial secretion of vinblastine by human intestinal adenocarcinoma cell (HCT-8 and T84) layers expressing P-glycoprotein. Er. J. Cancer 1991, 64, 437-444.
80. Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J. Med. Chem. 1995, 38, 3193-3196.
81. Zhang, Y.; Guo, X.; Lin, E. T.; Benêt, L. Z. Overlapping substrate specificity of cytochrome P450 3A and P-glycopro-tein for a novel cysteine protease inhibitor. Drug Metab. Dispos. 1998, 26, 360-366.
82. Sparreboom, A.; van Asperen, J.; Mayer, U.; Schinkel, A. H.; Smit, J. W.; Meijer, D. K. F.; Borst, P.; Nooijen, W. J.; Beijnen, J. H.; van Tellingen, 0. Limited oral bioavailability of taxol and active epithelial excretion of paclitaxel (Taxol ) caused by P-glycoprotein in the intestine. Froc. Natl. Acad. Sei. U.S.A. 1997, 94, 2031-2035.
83. van Asperen, J.; van Tellingen, O.; Sparreboom, A.; Schinkel, A. H.; Borst, P.; Nooijen, W. J.; Beijnen, J. H. Enhanced oral bioavailability of paclitaxel in mice treated with the Pglycoprotein blocker SDZ PSC 833. Br. J. Cancer 1997, 76, 1181-1183.