Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery
Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery
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DOI：
10.1016/0168-3659(95)00147-6
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发表时间：
1996-05-01
影响因子：
10.8
通讯作者：
Wacher, VJ
中科院分区：
文献类型：
--
作者：
Benet, LZ;Wu, CY;Wacher, VJ
许多药物的口服生物利用度差通常归因于在胃肠液中的溶解度差、肠膜渗透性差和/或广泛的肝脏首过消除。然而，最近，人们已经认识到，细胞色素P-450 3A介导的药物在肠道中的代谢，和P-糖蛋白的逆向转运过程也可能显着有助于药物的生物利用度差。我们已经表明，环孢菌素，一种高脂溶性的大分子量化合物，似乎没有吸收问题，目前的商业制剂的约86%在健康志愿者中被完整吸收。相反，环孢菌素的低生物利用度是由于在肠道中广泛的代谢提取（接近60%）。最近，已经确定了细胞色素P-450 3A的肠道代谢底物和P-糖蛋白的肠道反向转运底物之间存在很大的重叠，这表明这些过程可能共同作用，限制了大量原料药的生物利用度。认识到肠道中代谢和逆转运过程的这种潜力，导致了改善药物生物利用度的新观点，这与传统的物理化学方法不同。
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.