Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics

J Pharm Sci. 1998 Nov;87(11):1322-30. doi: 10.1021/js980082d.


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.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Cyclosporine / pharmacokinetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dipeptides / pharmacokinetics
  • Humans
  • Intestinal Absorption / physiology
  • Intestine, Small / metabolism*
  • Morpholines / pharmacokinetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • Peptides / pharmacokinetics*
  • Saquinavir / pharmacokinetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Dipeptides
  • Morpholines
  • Peptides
  • ko2 mu-urea-phe-hphe vinylsulfone
  • Cyclosporine
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Saquinavir