The drug efflux-metabolism alliance: biochemical aspects

Adv Drug Deliv Rev. 2001 Oct 1:50 Suppl 1:S3-11. doi: 10.1016/s0169-409x(01)00178-8.


The considerable overlap in the substrate selectivity and tissue localization of CYP3A and P-glycoprotein has led to the hypothesis that this transporter and enzyme pair act as a coordinated absorption barrier against xenobiotics. A historical perspective on the investigation of this interactive alliance is given, starting from the understanding of the role of intestinal metabolism in explaining cyclosporine clinical data. Several animal studies using mdr1a-/- knockout mice have demonstrated P-glycoprotein's importance in limiting drug absorption and decreasing bioavailability. Human clinical studies investigating the importance of intestinal CYP3A and P-glycoprotein through inhibition or induction of these proteins have provided further evidence of this interaction. Recent in vitro studies using CYP3A4-expressing Caco-2 cells are reported. These studies reveal that the role of P-glycoprotein in the intestine extends beyond simply limiting parent drug absorption but also includes increasing the access of drug to metabolism by CYP3A through repeated cycles of absorption and efflux.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Biological Availability
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Immunosuppressive Agents / pharmacokinetics
  • Intestinal Absorption / physiology*
  • Oxidoreductases, N-Demethylating / metabolism
  • Pharmaceutical Preparations / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating