Kinetic analyses for species differences in P-glycoprotein-mediated drug transport
Kinetic analyses for species differences in P-glycoprotein-mediated drug transport
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DOI：
10.1002/jps.20686
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发表时间：
2006-12-01
影响因子：
3.8
通讯作者：
Yokoi, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Katoh, Miki;Suzuyama, Naoto;Yokoi, Tsuyoshi
P-糖蛋白(P-gp)在药物的药代动力学中起着重要的作用。关于P-gp介导的药物转运活性的物种差异的信息很少。本研究的目的是利用人、猴、犬、大鼠(MDR1a和MDR1b)和小鼠(MDR1a和MDR1b)的7个多药耐药(MDR1)转基因细胞系，阐明P-gp介导的药物转运活性的动力学参数的差异和物种差异的存在。地尔硫卓、环孢菌素A和地塞米松在mdr1细胞单层中的跨细胞转运。地尔硫卓在7种细胞系中的表观K值相差约16.5倍。在地尔硫卓转运方面，经P-gp表达水平校正的人P-gp的V-max/K-m值与猴P-gp相近，但比犬P-gp高5.6倍。人P-gp对环孢素A转运的校正V-max/K-m值是猴P-gp的3.8倍。本研究对于在相同的实验条件下评价不同动物的P-gp功能具有一定的参考价值。用校正的V-max/K-m值评价P-gp介导的药物转运活性的物种差异因底物不同而不同。(C)2006年Wiley-Liss，Inc.
P-glycoprotein (P-gp) plays an important role in the pharmacokinetics of drugs. There is little information on the species differences in P-gp-mediated drug transport activity. The purpose of the present study was to clarify the differences in the kinetic parameters and the existence of species differences in the P-gp-mediated drug transport activity using seven multidrug resistence1 (MDR1) transfected cell lines, in which the cDNA was from human, monkey, canine, rat (MDR1a and MDR1b), and mouse (mdr1a and mdr1b). The transcellular transport of diltiazem, cyclosporin A, and dexamethasone across monolayers of MDR1 transfected cells. The apparent K. values of diltiazem exhibited approximately 16.5-fold differences among the seven cell lines. Concerning the diltiazem transport, the V-max/K-m value of human P-gp corrected by the P-gp expression level was similar to that of monkey P-gp, but was 5.6-fold higher than that of canine P-gp. On the other hand, the corrected V-max/K-m value of human P-gp for cyclosporin A transport was 3.8-fold higher than that of monkey P-gp. The present study would be valuable to evaluate the P-gp function of various animals in the same experimental condition. It was clarified that the species differences in P-gp-mediated drug transport activity evaluated by the corrected V-max/K-m value differed according to the substrate. (c) 2006 Wiley-Liss, Inc.