RT Journal Article SR Electronic T1 Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides: In Vitro, In Vivo, and In Vitro-to-In Vivo Extrapolation JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 673 OP 685 DO 10.1124/jpet.112.200691 VO 344 IS 3 A1 Shen, Hong A1 Yang, Zheng A1 Mintier, Gabe A1 Han, Yong-Hae A1 Chen, Cliff A1 Balimane, Praveen A1 Jemal, Mohammed A1 Zhao, Weiping A1 Zhang, Renjie A1 Kallipatti, Sanjith A1 Selvam, Sabariya A1 Sukrutharaj, Sunil A1 Krishnamurthy, Prasad A1 Marathe, Punit A1 Rodrigues, A. David YR 2013 UL http://jpet.aspetjournals.org/content/344/3/673.abstract AB 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 IC50 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 Km and RIF IC50) 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.