The drug transporter-metabolism alliance: uncovering and defining the interplay

Mol Pharm. 2009 Nov-Dec;6(6):1631-43. doi: 10.1021/mp900253n.


Two decades ago the importance of transporter-enzyme interplay and its effects on drug bioavailability and hepatic disposition were first recognized. Here we review the history of uncovering and defining this interplay with a primary emphasis on studies from our laboratory. We review the early 1990s oral bioavailability studies that found that the highly lipophilic, poorly water-soluble cyclosporine formulation on the market at that time did not have an absorption problem, but rather a gut metabolism problem. This led to studies of the interactive nature of CYP3A and P-glycoprotein in the intestine, and investigations of this interplay using cellular systems and isolated perfused rat organ studies. Studies investigating uptake transporter-enzyme interactions using cellular, perfused rat liver and intact rats are reviewed, followed by the human transporter-enzyme interaction studies. Work characterizing the rate limiting processes in the drug transporter-metabolism alliance is then addressed, ending with a review of areas of the interplay that require further studies and analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Biological Transport / physiology*
  • Cytochrome P-450 CYP3A / metabolism
  • Humans
  • Immunosuppressive Agents
  • Membrane Transport Proteins / metabolism*
  • Models, Biological
  • Protein Binding / physiology
  • Rats


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Membrane Transport Proteins
  • Cytochrome P-450 CYP3A