Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery

被引:164
作者
Benet, LZ [1 ]
Wu, CY [1 ]
Hebert, MF [1 ]
Wacher, VJ [1 ]
机构
[1] AUMAX INC, MENLO PK, CA 94025 USA
关键词
cytochrome P450 3A; P-glycoprotein; gut metabolism; counter-transport; cyclosporin;
D O I
10.1016/0168-3659(95)00147-6
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Poor oral bioavailability for many drugs is generally attributed to poor solubility in the gastrointestinal fluids, poor gut membrane permeability and/or extensive hepatic first-pass elimination. Recently, however, it has been recognized that cytochrome P-450 3A mediated drug metabolism in the intestine, and P-glycoprotein counter-transport processes may also contribute significantly to poor drug bioavailability. We have shown that cyclosporin, a highly lipid soluble, large molecular weight compound does not appear to have absorption problems, with approximately 86% of the present commercial formulation being absorbed intact in healthy volunteers. Rather, the low bioavailability of cyclosporin results from extensive metabolic extraction in the gut which approaches 60%. Recently, a strong overlap has been identified between substrates for gut metabolism by cytochrome P-450 3A and gut counter-transport by P-glycoprotein, suggesting that these processes may work together to limit the bioavailability of a large number of drug substances. Recognition of this potential for metabolism and counter-transport process in the gut leads to a new perspective on improving drug bioavailability that differs from the traditional physico-chemical approach.
引用
收藏
页码:139 / 143
页数:5
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