Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald, 17487 Greifswald, Germany.
Mol Pharm. 2012 Sep 4;9(9):2577-81. doi: 10.1021/mp3001815. Epub 2012 Aug 1.
Although pharmaceutical excipients are supposed to be pharmacologically inactive, solubilizing agents like Cremophor EL have been shown to interact with cytochrome P450 (CYP)-dependent drug metabolism as well as efflux transporters such as P-glycoprotein (ABCB1) and multidrug resistance associated protein 2 (ABCC2). However, knowledge about their influence on the function of uptake transporters important in drug disposition is very limited. In this study we investigated the in vitro influence of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on the organic anion transporting polypeptides (OATP) 1A2, OATP2B1, OATP1B1, and OATP1B3 and the Na(+)/taurocholate cotransporting polypeptide (NTCP). In stably transfected human embryonic kidney cells we analyzed the competition of the excipients with the uptake of bromosulfophthalein in OATP1B1, OATP1B3, OATP2B1, and NTCP, estrone-3-sulfate (E(3)S) in OATP1A2, OATP1B1, and OATP2B1, estradiol-17β-glucuronide in OATP1B3, and taurocholate (TA) in OATP1A2 and NTCP cells. SOL and CrEL were the most potent inhibitors of all transporters with the strongest effect on OATP1A2, OATP1B3, and OATP2B1 (IC(50) < 0.01%). HPCD also strongly inhibited all transport proteins but only for substrates containing a sterane-backbone. Finally, PEG seems to be a selective and potent modulator of OATP1A2 with IC(50) values of 0.05% (TA) and 0.14% (E(3)S). In conclusion, frequently used solubilizing agents were shown to interact substantially with intestinal and hepatic uptake transporters which should be considered in drug development. However, the clinical relevance of these findings needs to be evaluated in further in vivo studies.
虽然药用辅料被认为在药理学上是无活性的，但增溶剂如 Cremophor EL 已被证明可与细胞色素 P450（CYP）依赖性药物代谢以及外排转运蛋白如 P-糖蛋白（ABCB1）和多药耐药相关蛋白 2（ABCC2）相互作用。然而，关于它们对药物处置中重要摄取转运体功能的影响的知识非常有限。在这项研究中，我们研究了聚乙二醇 400（PEG）、羟丙基-β-环糊精（HPCD）、Solutol HS 15（SOL）和 Cremophor EL（CrEL）对有机阴离子转运多肽（OATP）1A2、OATP2B1、OATP1B1 和 OATP1B3 以及钠离子/牛磺胆酸盐协同转运蛋白（NTCP）的体外影响。在稳定转染的人胚肾细胞中，我们分析了赋形剂与溴磺酞在 OATP1B1、OATP1B3、OATP2B1 和 NTCP 中的摄取、雌酮-3-硫酸盐（E（3）S）在 OATP1A2、OATP1B1 和 OATP2B1 中的摄取、雌二醇-17β-葡糖苷酸在 OATP1B3 中的摄取以及牛磺胆酸盐（TA）在 OATP1A2 和 NTCP 细胞中的摄取的竞争。SOL 和 CrEL 是所有转运蛋白中最有效的抑制剂，对 OATP1A2、OATP1B3 和 OATP2B1 的作用最强（IC（50）<0.01%）。HPCD 也强烈抑制所有转运蛋白，但仅对含有甾体骨架的底物起作用。最后，PEG 似乎是 OATP1A2 的选择性和有效调节剂，IC（50）值分别为 0.05%（TA）和 0.14%（E（3）S）。总之，常用的增溶剂已被证明与肠道和肝脏摄取转运体有实质性相互作用，在药物开发过程中应予以考虑。然而，这些发现的临床相关性需要在进一步的体内研究中进行评估。
