Role of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics

doi:10.1021/js980082d

Journal of Pharmaceutical Sciences

Volume 87, Issue 11, November 1998, Pages 1322-1330

https://doi.org/10.1021/js980082d Get rights and content

Abstract

Cytochrome P450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene product P-glycoprotein (P-gp) are present at high concentrations in villus tip enterocytes of the small intestine and share a significant overlap in substrate specificity. A large body of research both in vitro and in vivo has established metabolism by intestinal CYP3A4 as a major determinant of the systemic bioavailability of orally administered drugs. More recently it has been recognized that drug extrusion by intestinal P-gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A-mediated metabolism. There is relatively little data regarding the effects of CYP3A and P-gp on peptide drugs; however, studies with the cyclic peptide immunosuppresant cyclosporine as well as peptidomimetics such as the HIV-protease inhibitor saquinavir (Invirase) and a new cysteine protease inhibitor K02 (Morpholine-Urea-Phe-Hphe-Vinyl sulfone; Axys Pharmaceuticals) provide some insight into the impact of these systems on the oral absorption of peptides.

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^†: Presented at the ACS Conference on Formulations and Drug Delivery II, La Jolla, California, October 5-8, 1997.

^‡: AvMax Inc.

^§: University of California.

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Conference ReportsRole of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics†

Abstract

Adv. Drug Delivery Rev.

J. Biol. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

FEBS Lett.

Pharmacol. Ther.

Biochem. Pharma-col.

Lancet

J. Immunol. Methods

J. Immunol. Methods

Interindividual variations in human liver cyto-chrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver mi-crosomes of 30 Japanese and 30 caucasians

J. Pharmacol. Exp. Ther.

Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man

J. Clin. Invest.

Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and cancer chemotherapy

Mol. Carcinog.

Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination

An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials

Toxicol. Pathol.

P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature

Pharmaco-genetics

Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase

DNA

Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control

Eur. J. Biochem.

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Mol. Pharmacol.

Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol

Pharmacol.

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J. Biochem.

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Biochemistry

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Pharmacogenetics

Identification of an inducible form of cytochrome P-450 in human liver

Proc. Natl. Acad. Sci. U.S.A.

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Proc. Natl. Acad. Sci. U.S.A.

Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins

Cancer Res.

Drug metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P450

Pediatr. Pharmacol.

Regioselective biotransformation of mida-zolam by members of the human cytochrome P450 3A (CYP3A) subfamily

Biochem. Pharmacol.

Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes

J. Clin. Invest.

Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes

Hepatology

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Modulators and substrates of P-glycoprotein and cytochrome P450 3A coordinately upregulate these proteins in human colon carcinomas

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Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients

J. Pharmacol. Exp. Ther.

Conference Reports
Role of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics^†