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The Gut as a Barrier to Drug Absorption

Combined Role of Cytochrome P450 3A and P-Glycoprotein

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Abstract

Intestinal phase I metabolism and active extrusion of absorbed drug have recently been recognised as major determinants of oral bioavailability. Cytochrome P450 (CYP) 3A, the major phase I drug metabolising enzyme in humans, and the multidrug efflux pump, P-glycoprotein, are present at high levels in the villus tip of enterocytes in the gastrointestinal tract, the primary site of absorption for orally administered drugs. The importance of CYP3A and P-glycoprotein in limiting oral drug delivery is suggested to us by their joint presence in small intestinal enterocytes, by the significant overlap in their substrate specificities, and by the poor oral bioavailability of joint substrates for these 2 proteins. These proteins are induced or inhibited by many of the same compounds.

A growing number of preclinical and clinical studies have demonstrated that the oral bioavailability of many CYP3A and/or P-glycoprotein substrate drugs can be increased by concomitant administration of CYP3A inhibitors and/or P-glycoprotein inhibitors. We believe that further understanding the physiology and biochemistry of the interactive nature of intestinal CYP3A and P-glycoprotein will be important in defining, controlling, and improving oral bioavailability of CYP3A/P-glycoprotein substrates.

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References

  1. Benet LZ, Wu CY, Hebert MF, et al. Intestinal drag metabolism and antitransport processes: a potential paradigm shift in oral drug delivery. J Controlled Release 1996; 39: 139–43

    Article  CAS  Google Scholar 

  2. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–34

    Article  PubMed  CAS  Google Scholar 

  3. Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol 1996; 49:311–8

    PubMed  CAS  Google Scholar 

  4. Kolars JC, Awni WM, Merion RM, et al. First-pass metabolism of cyclosporine by the gut. Lancet 1991; 338: 1488–90

    Article  PubMed  CAS  Google Scholar 

  5. Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 1996; 60: 14–24

    Article  PubMed  CAS  Google Scholar 

  6. Thummel KE, O’shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 1996;59:491–502

    Article  PubMed  CAS  Google Scholar 

  7. Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr 1 ) in interpatient variation in the oral bioavailability of cyclosporine A. Clin Pharmacol Ther 1997; 62: 248–60

    Article  PubMed  CAS  Google Scholar 

  8. Masuda S, Uemoto S, Hashida T, et al. Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther 2000; 68: 98–103

    Article  PubMed  CAS  Google Scholar 

  9. Gomez DY, Wacher VJ, Tomlanovich SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995; 58: 15–9

    Article  PubMed  CAS  Google Scholar 

  10. Floren LC, Bekersky I, Benet LZ, et al. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 1997; 62: 41–9

    Article  PubMed  CAS  Google Scholar 

  11. Floren LC, Christians U, Zimmerman JJ, et al. Sirolimus oral bioavailability increases ten-fold with concomitant ketoconazole. Clin Pharmacol Ther 1999; 65: 159

    Article  Google Scholar 

  12. Westphal K, Weinbrenner A, Giessmann T, et al. Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein. Clin Pharmacol Ther 2000; 68: 6–12

    Article  PubMed  CAS  Google Scholar 

  13. Boyd RA, Stern RH, Stewart BH, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 2000; 40: 91–8

    Article  PubMed  CAS  Google Scholar 

  14. Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–7

    Article  PubMed  CAS  Google Scholar 

  15. Hebert MF, Fisher RM, Marsh CL, et al. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999;39:91–6

    Article  PubMed  CAS  Google Scholar 

  16. Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996; 59: 7–13

    Article  PubMed  CAS  Google Scholar 

  17. Holtbecker N, Fromm MF, Kroemer HK, et al. The nifedipinerifampin interaction, evidence for induction of gut wall metabolism. Drag Metab Dispos 1996; 24: 1121–3

    CAS  Google Scholar 

  18. van Asperen J, van Tellingen O, Sparreboom A, et al. Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer 1997; 76: 1181–3

    Article  PubMed  Google Scholar 

  19. Yamaji H, Matsumura Y, Yoshikawa Y, et al. Pharmacokinetic interactions between HIV protease inhibitors in rats. Biopharm Drug Dispos 1999; 20: 241–7

    Article  PubMed  CAS  Google Scholar 

  20. Lin JH, Chiba M, Chen I, et al. Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3A and P-glycoprotein induction. Drug Metab Dispos 1999; 27: 1187–93

    PubMed  CAS  Google Scholar 

  21. Salphati L, Benet LZ. Effects of ketoconazole on digoxin absorption and disposition in rats. Pharmacology 1998;56: 308–13

    Article  PubMed  CAS  Google Scholar 

  22. Song S, Suzuki H, Kawai R, et al. Effect of PSC 833, a P-glycoprotein modulator, on the disposition of vincristine and digoxin in rats. Drag Metab Dispos 1999; 27: 689–94

    CAS  Google Scholar 

  23. Zhang Y, Hsien Y, Izumi T, et al. Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats. J Pharmacol Exp Ther 1998; 287: 246–52

    PubMed  CAS  Google Scholar 

  24. Wrighton SA, VandenBranden M, Ring BJ. The human drag metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24: 461–73

    PubMed  CAS  Google Scholar 

  25. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JH, Limbird LE, Molinoff PB, et al., editors. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 1996: 3–28

    Google Scholar 

  26. Murray GI, Barnes TS, Sewell HF, et al. The immunocytochemical localization 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: 465–75

    Article  PubMed  CAS  Google Scholar 

  27. Haehner BD, Gorski JC, Vandenbranden M, et al. Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol 1996; 50: 52–9

    PubMed  CAS  Google Scholar 

  28. Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992; 90: 1871–8

    Article  PubMed  CAS  Google Scholar 

  29. Shimada T, Yamazaki H, Mimura M, et al. 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 1994; 270: 414–23

    PubMed  CAS  Google Scholar 

  30. Watkins PB, Wrighton SA, Schuetz EG, et al. Identification of glucocorticoid-inducible cytochrome P-450 in the intestine mucosa of rats and human. J Clin Invest 1987; 80: 1029–36

    Article  PubMed  CAS  Google Scholar 

  31. Williams JA, Chenery RJ, Berkhout TA, et al. Induction of cytochrome P4503A by the antiglucocorticoid mifepristone and a novel hypocholesterolaemic drug. Drug Metab Dispos 1997; 25: 757–61

    PubMed  CAS  Google Scholar 

  32. Lown KS, Kolars JC, Thummel KE, et al. 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

    PubMed  CAS  Google Scholar 

  33. Lehmann JM, McKee DD, Waston MA, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102: 1016–23

    Article  PubMed  CAS  Google Scholar 

  34. Blumberg B, Sabbagh Jr W, Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 1998; 12: 3195–205

    Article  PubMed  CAS  Google Scholar 

  35. Bertilsson G, Heidrich J, Svensson K, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3 A induction. Proc Natl Acad Sci USA 1998; 95: 12208–13

    Article  PubMed  CAS  Google Scholar 

  36. Chiba M, Hensleigh M, Lin JH. Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. Biochem Pharmacol 1997; 53: 1187–95

    Article  PubMed  CAS  Google Scholar 

  37. Fitzsimmons ME, Collins JM. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. Drug Metab Dispos 1997; 25: 256–66

    PubMed  CAS  Google Scholar 

  38. Kumar GN, Rodrigues AD, Buko AM, et al. Cytochrome P450-mediated metabolism of the HJV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 1996; 277: 423–31

    PubMed  CAS  Google Scholar 

  39. Li AP, Kaminski DL, Rasmussen A. Substrates of human hepatic cytochrome P450 3A4. Toxicology 1995; 104: 1–8

    Article  PubMed  CAS  Google Scholar 

  40. Perry CM, Benfield P. Nelfinavir. Drugs 1997; 54: 81–7; discussion 88

    Article  PubMed  CAS  Google Scholar 

  41. Smith DA, Jones BC. Speculations on the substrate structureactivity relationship (SSAR) of cytochrome P450 enzymes. Biochem Pharmacol 1992; 44: 2089–98

    Article  PubMed  CAS  Google Scholar 

  42. Ferenczy GG, Morris GM. The active site of cytochrome P-450 nifedipine oxidase: a model-building study. J Mol Graph 1989;7:206–11

    Article  PubMed  CAS  Google Scholar 

  43. Shou M, Grogan J, Mancewicz JA, et al. Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site. Biochemistry 1994; 33: 6450–5

    Article  PubMed  CAS  Google Scholar 

  44. de Waziers PH, Cugnenc PH, Yang CS, et al. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253: 387–94

    PubMed  Google Scholar 

  45. Paine MF, Khalighi M, Fisher JM, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 1997; 283: 1552–62

    PubMed  CAS  Google Scholar 

  46. Wacher VJ, Silverman JA, Zhang Y, et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of Peptides and peptidomimetics. J Pharm Sci 1998;87: 1322–30

    Article  PubMed  CAS  Google Scholar 

  47. Lown KS, Ghosh M, Watkins PB. Sequence of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab Dispos 1998; 26: 185–7

    PubMed  CAS  Google Scholar 

  48. Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol 1992; 8: 67–113

    Article  PubMed  CAS  Google Scholar 

  49. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152–62

    Article  PubMed  CAS  Google Scholar 

  50. Patel NH, Rothenberg ML. Multidrug resistance in cancer chemotherapy. Invest New Drugs 1994; 12: 1–13

    Article  PubMed  CAS  Google Scholar 

  51. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427

    Article  PubMed  CAS  Google Scholar 

  52. Silverman JA, Schrenk D. Hepatic canalicular membrane 4: expression of the multidrug resistance genes in the liver. FASEB J 1997; 11:308–13

    PubMed  CAS  Google Scholar 

  53. Cordon-Cardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277–87

    Article  PubMed  CAS  Google Scholar 

  54. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84:7735–8

    Article  PubMed  CAS  Google Scholar 

  55. Schinkel AH, Smit JJ, van Teilingen O, et al. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502

    Article  PubMed  CAS  Google Scholar 

  56. Schinkel AH, Mol CA, Wagenaar E, et al. Multidrug resistance and the role of P-glycoprotein knockout mice. Eur J Cancer 1995; 31A: 1295–8

    Article  PubMed  CAS  Google Scholar 

  57. Schumacher U, Mollgard K. The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain. Histochem Cell Biol 1997; 108: 179–82

    Article  PubMed  CAS  Google Scholar 

  58. Schuetz EG, Schinkel AH, Relling MV, et al. P-glycoprotein, a major determinant of rifampicin-inducible expression of cytochrome P450 3A in mice and humans. Proc Natl Acad Sci USA 1996; 93: 4001–5

    Article  PubMed  CAS  Google Scholar 

  59. Silverman JA, Thorgeirsson SS. Regulation and function of the multidrug resistance genes in liver. Prog Liver Dis 1995; 13: 101–23

    PubMed  CAS  Google Scholar 

  60. Rosenberg MF, Callaghan R, Ford RC, et al. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 1997; 272: 10685–94

    Article  PubMed  CAS  Google Scholar 

  61. Fojo AT, Ueda K, Slamon DJ, et al. Expression of a multidrugresistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84: 265–9

    Article  PubMed  CAS  Google Scholar 

  62. Sparreboom A, van Asperen J, Mayer U, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 1997; 94: 2031–5

    Article  PubMed  CAS  Google Scholar 

  63. Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101: 289–94

    Article  PubMed  CAS  Google Scholar 

  64. Kim RB, Wandel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408–14

    Article  PubMed  CAS  Google Scholar 

  65. Benet LZ, Izumi T, Zhang Y, et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Controlled Release 1999; 62: 25–31

    Article  CAS  Google Scholar 

  66. Palkama VJ, Ahonen J, Neuvonen PJ, et al. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999; 66: 33–9

    Article  PubMed  CAS  Google Scholar 

  67. Heizmann P, Ziegler WH. Excretion and metabolism of 14C-midazolam in humans following oral dosing. Arzneimittel Forschung 1981; 31: 2220–3

    PubMed  CAS  Google Scholar 

  68. Wu CY, Benet LZ, Hebert MF, et al. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 1995; 58: 492–7

    Article  PubMed  CAS  Google Scholar 

  69. Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 1989; 36: 89–96

    PubMed  CAS  Google Scholar 

  70. Gorski JC, Jones DR, Haehner-Daniels BD, et al. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and Clarithromycin. Clin Pharmacol Ther 1998; 64: 133–43

    Article  PubMed  CAS  Google Scholar 

  71. Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104: 147–53

    Article  PubMed  CAS  Google Scholar 

  72. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–8

    Article  PubMed  CAS  Google Scholar 

  73. Takanaga H, Ohnishi A, Yamada S, et al. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J Pharmacol Exp Ther 2000; 293: 230–6

    PubMed  CAS  Google Scholar 

  74. Dantzig AH, Shepard RL, Law KL, et al. Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther 1999; 290: 854–62

    PubMed  CAS  Google Scholar 

  75. Achira M, Suzuki H, Ito K, et al. Comparative studies to determine selective inhibitor for P-glycoprotein and cytochrome P450 3A4 [online]. AAPS PharmSci 2000; 4

  76. Hall SD, Thummel KE, Watkins PB, et al. Molecular and physical mechanisms of first-pass extraction. J Pharmacol Exp Ther 1999; 27: 161–6

    CAS  Google Scholar 

  77. Bailey DG, Malcolm J, Arnold O, et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10

    Article  PubMed  CAS  Google Scholar 

  78. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545–53

    Article  PubMed  CAS  Google Scholar 

  79. Ito K, Kusuhara H, Sugiyama Y Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption: theoretical approach. Pharm Res 1999; 16: 225–31

    Article  PubMed  CAS  Google Scholar 

  80. Almquist KC, Loe DW, Hipfner DR, et al. Characterization of the M(r) 190,000 multidrug resistance protein (MRP) in drugselected and transfected human tumor cell. Cancer Res 1995; 55: 102–10

    PubMed  CAS  Google Scholar 

  81. Adibi SA. The Oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology 1997; 113: 332–40

    Article  PubMed  CAS  Google Scholar 

  82. Zhang L, Dresser MJ, Gray AT, et al. Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 1997;51:913–21

    PubMed  CAS  Google Scholar 

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Zhang, Y., Benet, L.Z. The Gut as a Barrier to Drug Absorption. Clin Pharmacokinet 40, 159–168 (2001). https://doi.org/10.2165/00003088-200140030-00002

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