Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA.
J Pharmacol Exp Ther. 2013 Mar;344(3):673-85. doi: 10.1124/jpet.112.200691. Epub 2013 Jan 7.
Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17β-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC(50) values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K(m) and RIF IC(50)) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting.
有机阴离子转运多肽（OATP）1B1、1B3 和 2B1 可作为药物相互作用（DDI）的作用部位。在本工作中，评估食蟹猴是否可作为研究 OATP 介导的 DDI 的潜在模型。克隆、表达并鉴定了三种食蟹猴 OATPs（cOATPs），其与相应的人 OATPs（hOATPs）的氨基酸序列同源性较高（OATP1B1、1B3 和 2B1 分别为 91.9%、93.5%和 96.6%）。cOATPs 稳定转染入人胚肾细胞，其功能与人 OATPs（hOATPs）相似，这从典型底物（雌二醇-17β-d-葡糖苷酸、胆囊收缩素八肽和雌酮-3-硫酸盐）的摄取率相似可以看出。此外，六种已知的 hOATP 抑制剂对 cOATPs 的抑制作用也具有相似的 IC50 值。为了进一步评估食蟹猴作为模型的适宜性，体外考察了一种已知的 hOATP 底物[瑞舒伐他汀（RSV）]-抑制剂[利福平（RIF）]对。猴衍生参数（RSV Km 和 RIF IC50）与用人 OATPs 和人原代肝细胞获得的参数相似（在 3.5 倍以内）。在体内，单次给予利福平（15mg/kg，口服） 1 小时后口服 RSV（3mg/kg）的血浆浓度-时间曲线下面积增加 2.9 倍，与在人体内观察到的（3.0 倍）一致。还探讨了一些基于考虑受影响途径的分数和游离与总抑制剂浓度的体外-体内外推方法。结论是，食蟹猴具有作为非临床评估 OATP 介导的 DDI 有用模型的潜力。
