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

Abstract

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-17b-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. IntroductionDrug-drug interactions (DDIs) have often been attributed to cytochrome P450 (P450) enzymes because of their prominent role in the metabolic clearance of drugs (Vuppugalla et al., 2010). More recently, however, attention has turned to active transport processes in different organs and the close interplay between drug transport and metabolism at the cellular level. In particular, organic anion-transporting polypeptides (OATPs) are known to mediate the active uptake of numerous drugs into hepatocytes and hence govern their overall clearance, pharmacokinetic profile, and liver-toplasma ratio (Giacomini et al., 2010;Fenner et al., 2012;Yoshida et al., 2012).OATPs can also serve as the loci of important DDIs leading to changes in systemic and local drug concentrations, possibly resulting in altered efficacy and enhanced toxicity (Giacomini et al., 2010;Yoshida et al., 2012). For example, cyclosporine A (CsA) increases the area under the concentration-time curve (AUC) (∼15-fold) and C max (∼14-fold) of atorvastatin in s This article has supplemental material available at jpet.aspetjournals.org.ABBREVIATIONS: AUC, area under the concentration-time curve; CCK-8, cholecystokinin octapeptide; CI, confidence interval; cOATP, cynomolgus organic anion-transporting polypeptide; CsA, cyclosporine A; DDI, drug-drug inter...

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

“…Therefore, it was suggested that the relative expression levels of these OATPs in liver are similar between cynomolgus monkeys and humans. In addition, high levels of homology have been reported among gene and amino acid sequences for these OATPs between the species (White et al, 2006;Ebeling et al, 2011;Utoh et al, 2012), and also it has been suggested that these OATPs substrate and inhibitor profiles were similar between the species (White et al, 2006;Maeda and Sugiyama, 2010;Shen et al, 2013).…”

“…However, high levels of homology among gene and amino acid sequences (.95% and .93%, respectively) have recently been reported for OATP1B1 and OATP1B3 between humans and cynomolgus monkeys (White et al, 2006;Ebeling et al, 2011;Utoh et al, 2012). In in vitro functional characterization studies, it has been suggested that cynomolgus monkey OATP1B1, OATP1B3 substrate and inhibitor profiles were similar to those of humans (White et al, 2006;Maeda and Sugiyama, 2010;Shen et al, 2013). Hence, monkeys may be useful as a preclinical in vivo DDI model involving OATP inhibition.…”

“…The usefulness of cynomolgus monkeys to assess DDIs using rosuvastatin as an OATP substrate has been reported (Shen et al, 2013). However, those investigators used only orally administered rosuvastatin in combination with an OATP inhibitor, where the fraction absorbed and the intestinal availability of rosuvastatin were not known; therefore, it was not possible to estimate alterations associated only with the effect in the liver.…”

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

“…A recent study with a large set of well-characterized, structurally diverse compounds concluded that monkey was superior to dog or/and rat in all the methods tested, presumably because monkey is evolutionarily closest to human (Lombardo et al, 2013b). Both uptake and efflux transporters in monkey have been shown to be more predictive of human than rodents and dogs (Syvänen et al, 2009;Shen et al, 2013). The Øie-Tozer model gave the best prediction compared with the other methods.…”

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

“…All transport experiments were performed manually in a 24-well plate on a thermostatic VWR symphony incubating microplate shaker (VWR, Thorofare, NJ) calibrated at 37°C following the protocol described previously with minor modifications (Shen et al, 2013). In brief, cells grown in 24-well plates were rinsed twice with 1.5 ml of prewarmed HBSS.…”