期刊
MOLECULAR PHARMACEUTICS
卷 6, 期 6, 页码 1631-1643出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp900253n
关键词
Transporters; metabolic enzymes; transporter-enzyme interplay; intestine; liver; Biopharmaceutics Drug Disposition System; BDDCS; atorvastatin; cyclosporine; digoxin; erythromycin; felodipine; glyburide; midazolam; rifampin; sirolimus; tacrolimus
资金
- NIH [GM075900, GM061390]
- Amgen
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.
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