TY - JOUR T1 - Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides (OATPs): In Vitro, In Vivo and In Vitro-to-In Vivo Extrapolation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.200691 SP - jpet.112.200691 AU - Hong Shen AU - Zheng Yang AU - Gabe Mintier AU - Yong-Hae Han AU - Cliff Chen AU - Praveen Balimane AU - Mohammed Jemal AU - Weiping Zhao AU - Renjie Zhang AU - Sanjith Kallipatti AU - Sabariya Selvam AU - Sunil Sukrutharaj AU - Prasad Krishnamurthy AU - Punit Marathe AU - David A Rodrigues Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/01/07/jpet.112.200691.abstract N2 - Organic anion transporting polypeptides (OATP) 1B1, 1B3 and 2B1 can serve as the loci of drug-drug interactions (DDIs). Therefore, 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, 6 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 and 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) 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 vs. total inhibitor concentrations, were explored also. 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. ER -