The drug transporter-metabolism alliance: uncovering and defining the interplay.
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.
Benet
Leslie Z
LZ
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California 94143-0912, USA. leslie.benet@ucsf.edu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding / Q000502:physiology; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; D051544:Cytochrome P-450 CYP3A