The Drug Transporter−Metabolism Alliance: Uncovering and Defining the Interplay

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• 作者：Leslie Z. Benet
• 刊名：Molecular Pharmaceutics
• 出版年：2009
• 出版时间：December 7, 2009
• 年：2009
• 卷：6
• 期：6
• 页码：1631-1643
• 全文大小：350K
• 年卷期：v.6,no.6(December 7, 2009)
• ISSN：1543-8392

文摘

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.