Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.).
Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)
J Pharmacol Exp Ther. 2018 Jul;366(1):37-45. doi: 10.1124/jpet.117.247254. Epub 2018 Apr 13.
Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multiexperimental in vitro and in vivo approach. Atovaquone uptake was not elevated in HEK293 cells singly overexpressing OATP1B1, OATP1B3, OATP2B1, OCT1, NTCP, or OAT2. Hepatocyte uptake of atovaquone was not impaired by OATP and OCT inhibitor cocktail (rifamycin and imipramine). Atovaquone liver-to-blood ratio at distributional equilibrium was not reduced in Oatp1a/1b and Oct1/2 knockout mice. Atovaquone exhibited efflux ratios of approximately unity in P-gp and BCRP overexpressing MDCK cell monolayers and did not display enhanced uptake in MRP2 vesicles. Biliary and canalicular clearance were not decreased in P-gp, Bcrp, Mrp2, and Bsep knockout rats. In the present study, we rule out the involvement of major known basolateral uptake and bile canalicular efflux transporters in the hepatic uptake and biliary excretion of atovaquone. This is the first known example of a drug cleared by biliary excretion in humans, with extensive biliary concentration, which is not transported by the mechanisms investigated herein.
阿托伐醌是一种抗原生动物和抗肺囊虫药物，主要通过胆汁排泄未改变的原形药物清除。阿托伐醌在人胆汁中的浓度相对于游离血浆高出 10,000 倍。即使在对非特异性结合和胆汁中不完全溶解度进行校正后，阿托伐醌在胆汁中的浓度仍高出 100 倍，这与主动胆汁排泄一致。使用多种体外和体内实验方法研究了阿托伐醌的肝胆处置机制。单独过表达 OATP1B1、OATP1B3、OATP2B1、OCT1、NTCP 或 OAT2 的 HEK293 细胞中，阿托伐醌的摄取没有增加。OATP 和 OCT 抑制剂混合物（利福平和丙咪嗪）不会损害肝细胞摄取阿托伐醌。在 Oatp1a/1b 和 Oct1/2 敲除小鼠中，阿托伐醌在分布平衡时的肝血比没有降低。在过表达 P-糖蛋白和 BCRP 的 MDCK 细胞单层中，阿托伐醌的外排比约为 1，并且在 MRP2 小泡中没有显示出增强的摄取。在 P-糖蛋白、Bcrp、Mrp2 和 Bsep 敲除大鼠中，胆汁和胆管清除率没有降低。在本研究中，我们排除了主要已知的基底外侧摄取和胆汁管腔外排转运体参与阿托伐醌的肝摄取和胆汁排泄。这是第一个已知的在人类中通过胆汁排泄清除的药物，其具有广泛的胆汁浓度，而这些浓度不能通过本文研究的机制来转运。
