Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery
Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery
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DOI：
10.1016/s0168-3659(99)00034-6
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发表时间：
1999-11-01
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;Izumi, T;Wacher, VJ
细胞色素P-450 3A4 (CYP3A4)，人类主要的I期药物代谢酶，以及多药外排泵，MDR或p -糖蛋白（P-gp），在小肠绒毛尖端肠细胞中存在高水平，小肠绒毛尖端肠细胞是口服药物的主要吸收部位。这些蛋白质被许多相同的化合物诱导或抑制，并且在底物和抑制剂特异性上表现出广泛的重叠，这表明它们作为药物吸收的协同屏障。我们实验室对环孢素和他克莫司在人体中的一系列研究，以及一种新型半胱氨酸蛋白酶抑制剂在大鼠中的一系列研究，与CYP3A4和P-gp的抑制剂和诱诱剂一起给药，表明肠道提取可以通过肠道代谢和吸收率的测量来建模，后者反映P-gp的变化。对CYP3A底物药物咪达唑仑、茚地那韦、沙奎那韦和利福布汀的初步模型进行评估的结果表明，该模型可能有助于从体外数据预测体内肠道代谢。(C) 1999 Elsevier Science B.V.版权所有
Cytochrome P-450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the multidrug efflux pump, MDR or P-glycoprotein (P-gp), are present at high levels in the villus tip enterocytes of the small intestine, the primary site of absorption for orally administered drugs. These proteins are induced or inhibited by many of the same compounds and demonstrate a broad overlap in substrate and inhibitor specificities, suggesting that they act as a concerted barrier to drug absorption. A series of studies from our laboratory of cyclosporine and tacrolimus in humans and a novel cysteine protease inhibitor in rats, dosed concomitantly with inhibitors and inducers of CYP3A4 and P-gp, suggest that gut extraction can be modeled using measures of intestinal metabolism and absorption rate, the latter reflecting changes in P-gp. Results evaluating a preliminary model applied to the CYP3A substrate drugs midazolam, indinavir, saquinavir, and rifabutin suggest that the model may be useful for predicting in vivo intestinal metabolism from in vitro data. (C) 1999 Elsevier Science B.V. All rights reserved.