In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor
In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor
复制标题
DOI：
10.1124/dmd.112.048918
复制
发表时间：
2013-02-01
影响因子：
3.9
通讯作者：
Polli, Joseph W.
中科院分区：
文献类型：
--
作者：
Reese, Melinda J.;Savina, Paul M.;Polli, Joseph W.
度鲁特韦（DTG; S/GSK 1349572）是一种强效HIV-1整合酶抑制剂，具有独特的耐药性特征，每日一次给药方案不需要药代动力学加强。本工作研究了DTG的体外药物转运和代谢，并评估了临床药物相互作用的可能性。DTG是外排转运蛋白P-糖蛋白（Pgp）和人乳腺癌耐药蛋白（BCRP）的底物。其高的固有膜渗透性限制了这些转运蛋白对DTG肠道吸收的影响。尿苷二磷酸葡萄糖醛酸基转移酶（UGT）1A1是DTG体内代谢的主要酶，细胞色素P450（P450）3A4是一个重要的途径，UGT 1A3和UGT 1A9只是次要途径。DTG在体外对转运蛋白Pgp、BCRP、多药耐药蛋白2、有机阴离子转运多肽1B1/3、有机阳离子转运蛋白（OCT）1或药物代谢酶CYP 1A2、2A6、2B6、2C8、2C9、2C19、2D6、3A4、UGT 1A1或2B7几乎没有抑制作用（IC 50值> 30 μ M）。此外，在体外使用人肝细胞时，DTG未诱导CYP 1A2、2B6或3A4 mRNA。DTG确实抑制肾脏OCT 2（IC 50 = 1.9 μ M）转运蛋白，这为临床研究中观察到的血清肌酐轻度升高提供了机制基础。这些体外研究表明，DTG作为临床药物相互作用的肇事者的倾向较低，并为预测其他药物何时可能导致与DTG的药物相互作用提供了基础。
Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC50 values > 30 mu M) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC50 = 1.9 mu M) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.