Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein

Pharm Res. 1999 Mar;16(3):408-14. doi: 10.1023/a:1018877803319.


Purpose: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates.

Methods: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport.

Results: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin.

Conclusions: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Biological Transport
  • Caco-2 Cells
  • Cells, Cultured
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Resistance, Multiple
  • Enzyme Inhibitors / metabolism*
  • Humans
  • Male
  • Mice
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / metabolism*
  • Pharmacokinetics
  • Substrate Specificity


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