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Dissecting the Contribution of OATP1B1 to Hepatic Uptake of Statins Using the OATP1B1 Selective Inhibitor Estropipate
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-04-30 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b01226 Yueping Zhang 1 , Erika Panfen 1 , Marcus Fancher 1 , Michael Sinz 1 , Punit Marathe 1 , Hong Shen 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-04-30 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b01226 Yueping Zhang 1 , Erika Panfen 1 , Marcus Fancher 1 , Michael Sinz 1 , Punit Marathe 1 , Hong Shen 1
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Identification of a selective inhibitor of organic anion transporting polypeptide (OATP) 1B1 is critical in order to determine the contribution of OATP1B1-mediated uptake of investigational drugs into human hepatocytes for successful in vitro-to-in vivo extrapolation (IVIVE) of hepatic uptake and drug–drug interaction (DDI). The following study examined the inhibitory effects of estropipate (EPP) on major sinusoidal drug uptake transporters and explored its utility regarding IVIVE of statin hepatic disposition. EPP and its free-base form (i.e., estrone sulfate) showed a potent and high degree of selectivity in inhibiting the OATP1B1-mediated transport of rosuvastatin with an IC50 value averaging 0.05 ± 0.01 and 0.12 ± 0.07 μM for human and cynomolgus monkey OATP1B1 (hOATP1B1 and cOATP1B1), respectively, whereas weak inhibition was observed for human and monkey OATP1B3, OATP2B1, sodium-taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2, and organic cation transporter 1 with IC50 values ranging from 8.6 to 64.0 μM. EPP, together with rifamycin SV, was subsequently used to determine the fractions of hepatic uptake clearance (fT) of statins, including rosuvastatin, pitavastatin, and dehydropravastatin, which are reported to be mediated by OATP1B1, OATP1B3, OATP2B1, and NTCP. Finally, the magnitudes of in vivo inhibition of rosuvastatin clearance caused by EPP and rifampin in cynomolgus monkeys were predicted by using individual transporter IC50 and fT (AUC fold change 1.28 vs 1.21, 2.71 vs 1.75, and 3.35 vs 2.83, respectively). These results suggest that EPP is an appropriate OATP1B1-selective inhibitor to establish the relative contribution of OATP1B1 to hepatic uptake in vitro and to discern the role of OATP1B1 in hepatic disposition in vivo.
中文翻译：
剖析使用OATP1B1选择性抑制剂雌激素对OATP1B1对他汀类药物肝吸收的贡献
为了确定OATP1B1介导的研究药物对人肝细胞的摄取对肝细胞摄取和摄取的成功体外-体内外推（IVIVE）的贡献，鉴定有机阴离子转运多肽（OATP）1B1的选择性抑制剂至关重要。药物相互作用（DDI）。下列研究检查了雌激素（EPP）对主要正弦药物吸收转运蛋白的抑制作用，并探讨了其在IVIVE他汀类肝素处置中的效用。EPP及其游离碱形式（即硫酸雌酮）在用IC 50抑制OATP1B1介导的瑞舒伐他汀转运方面显示出强大而高度的选择性人和食蟹猴OATP1B1（hOATP1B1和cOATP1B1）的平均值分别为0.05±0.01和0.12±0.07μM，而对人和猴OATP1B3，OATP2B1，牛磺胆酸钠共转运多肽（NTCP），有机阴离子转运蛋白2的抑制作用较弱，以及有机阳离子转运蛋白1的IC 50值范围为8.6至64.0μM。EPP与利福霉素SV一起用于确定肝吸收清除率（f T）他汀类药物，包括瑞舒伐他汀，匹伐他汀和脱氢普伐他汀，据报道是由OATP1B1，OATP1B3，OATP2B1和NTCP介导的。最后，通过使用单个转运蛋白IC 50和f T（AUC倍数变化分别为1.28对1.21、2.71对1.75和3.35对2.83）来预测食蟹猕猴体内由EPP和利福平引起的瑞舒伐他汀清除的抑制程度。这些结果表明，EPP是一种合适的OATP1B1选择性抑制剂，可建立OATP1B1对体外肝吸收的相对作用，并识别OATP1B1在体内肝处置中的作用。
更新日期：2019-04-30
中文翻译：
剖析使用OATP1B1选择性抑制剂雌激素对OATP1B1对他汀类药物肝吸收的贡献
为了确定OATP1B1介导的研究药物对人肝细胞的摄取对肝细胞摄取和摄取的成功体外-体内外推（IVIVE）的贡献，鉴定有机阴离子转运多肽（OATP）1B1的选择性抑制剂至关重要。药物相互作用（DDI）。下列研究检查了雌激素（EPP）对主要正弦药物吸收转运蛋白的抑制作用，并探讨了其在IVIVE他汀类肝素处置中的效用。EPP及其游离碱形式（即硫酸雌酮）在用IC 50抑制OATP1B1介导的瑞舒伐他汀转运方面显示出强大而高度的选择性人和食蟹猴OATP1B1（hOATP1B1和cOATP1B1）的平均值分别为0.05±0.01和0.12±0.07μM，而对人和猴OATP1B3，OATP2B1，牛磺胆酸钠共转运多肽（NTCP），有机阴离子转运蛋白2的抑制作用较弱，以及有机阳离子转运蛋白1的IC 50值范围为8.6至64.0μM。EPP与利福霉素SV一起用于确定肝吸收清除率（f T）他汀类药物，包括瑞舒伐他汀，匹伐他汀和脱氢普伐他汀，据报道是由OATP1B1，OATP1B3，OATP2B1和NTCP介导的。最后，通过使用单个转运蛋白IC 50和f T（AUC倍数变化分别为1.28对1.21、2.71对1.75和3.35对2.83）来预测食蟹猕猴体内由EPP和利福平引起的瑞舒伐他汀清除的抑制程度。这些结果表明，EPP是一种合适的OATP1B1选择性抑制剂，可建立OATP1B1对体外肝吸收的相对作用，并识别OATP1B1在体内肝处置中的作用。
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