Eng Heather, Bi Yi-An, West Mark A, Ryu Sangwoo, Yamaguchi Emi, Kosa Rachel E, Tess David A, Griffith David A, Litchfield John, Kalgutkar Amit S, Varma Manthena V S
ADME Sciences, Medicine Design, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (H.E., Y.B., M.A.W., S.R., E.Y., R.E.K., M.V.S.V.), and PDM (D.A.T., J.L., A.S.K.) and Medicinal Chemistry, Medicine Design, Worldwide Research and Development (D.A.G.), Pfizer Inc., Cambridge, Massachusetts.
ADME Sciences, Medicine Design, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (H.E., Y.B., M.A.W., S.R., E.Y., R.E.K., M.V.S.V.), and PDM (D.A.T., J.L., A.S.K.) and Medicinal Chemistry, Medicine Design, Worldwide Research and Development (D.A.G.), Pfizer Inc., Cambridge, Massachusetts
J Pharmacol Exp Ther. 2021 Apr;377(1):169-180. doi: 10.1124/jpet.120.000457. Epub 2021 Jan 28.
It is generally presumed that uptake transport mechanisms are of limited significance in hepatic clearance for lipophilic or high passive-permeability drugs. In this study, we evaluated the mechanistic role of the hepato-selective organic anion-transporting polypeptides (OATPs) 1B1/1B3 in the pharmacokinetics of compounds representing large lipophilic acid space. Intravenous pharmacokinetics of 16 compounds with molecular mass ∼400-730 Da, logP ∼3.5-8, and acid pKa <6 were obtained in cynomolgus monkey after dosing without and with a single-dose rifampicin-OATP1B1/1B3 probe inhibitor. Rifampicin (30 mg/kg oral) significantly ( < 0.05) reduced monkey clearance and/or steady-state volume of distribution (VDss) for 15 of 16 acids evaluated. Additionally, clearance of danoprevir was reduced by about 35%, although statistical significance was not reached. A significant linear relationship was noted between the clearance ratio (i.e., ratio of control to treatment groups) and VDss ratio, suggesting hepatic uptake contributes to the systemic clearance and distribution simultaneously. In vitro transport studies using primary monkey and human hepatocytes showed uptake inhibition by rifampicin (100 µM) for compounds with logP ≤6.5 but not for the very lipophilic acids (logP > 6.5), which generally showed high nonspecific binding in hepatocyte incubations. In vitro uptake clearance and fraction transported by OATP1B1/1B3 (f) were found to be similar in monkey and human hepatocytes. Finally, for compounds with logP ≤6.5, good agreement was noted between in vitro f and clearance ratio (as well as VDss ratio) in cynomolgus monkey. In conclusion, this study provides mechanistic evidence for the pivotal role of OATP1B-mediated hepatic uptake in the pharmacokinetics across a wide, large lipophilic acid space. SIGNIFICANCE STATEMENT: This study provides mechanistic insight into the pharmacokinetics of a broad range of large lipophilic acids. Organic anion-transporting polypeptides 1B1/1B3-mediated hepatic uptake is of key importance in the pharmacokinetics and drug-drug interactions of almost all drugs and new molecular entities in this space. Diligent in vitro and in vivo transport characterization is needed to avoid the false negatives often noted because of general limitations in the in vitro assays while handling compounds with such physicochemical attributes.
一般认为，对于亲脂性或高被动通透性药物，摄取转运机制在肝脏清除中意义有限。在本研究中，我们评估了肝选择性有机阴离子转运多肽（OATPs）1B1/1B3在代表大亲脂性酸空间的化合物药代动力学中的机制作用。在食蟹猴中，分别在未给药和给予单剂量利福平（一种OATP1B1/1B3探针抑制剂）后，获得了16种分子量约为400 - 730 Da、logP约为3.5 - 8且酸pKa < 6的化合物的静脉药代动力学数据。利福平（30 mg/kg口服）显著（< 0.05）降低了所评估的16种酸中15种的猴子清除率和/或稳态分布容积（VDss）。此外，达诺普韦的清除率降低了约35%，尽管未达到统计学显著性。清除率比值（即对照组与治疗组的比值）与VDss比值之间存在显著的线性关系，表明肝脏摄取同时有助于全身清除和分布。使用原代猴和人肝细胞进行的体外转运研究表明，利福平（100 µM）对logP≤6.5的化合物有摄取抑制作用，但对亲脂性很强的酸（logP > 6.5）没有抑制作用，这类酸在肝细胞孵育中通常表现出高非特异性结合。发现OATP1B1/1B3在猴和人肝细胞中的体外摄取清除率和转运分数（f）相似。最后，对于logP≤6.5的化合物，食蟹猴的体外f与清除率比值（以及VDss比值）之间存在良好的一致性。总之，本研究为OATP1B介导的肝脏摄取在跨越广泛的大亲脂性酸空间的药代动力学中的关键作用提供了机制证据。意义声明：本研究为广泛的大亲脂性酸的药代动力学提供了机制性见解。有机阴离子转运多肽1B1/1B3介导的肝脏摄取在该空间中几乎所有药物和新分子实体的药代动力学及药物 - 药物相互作用中至关重要。在处理具有此类物理化学特性的化合物时，需要进行严谨的体外和体内转运特征研究，以避免因体外试验的一般局限性而经常出现的假阴性结果。
