Gene names: Solute carrier organic anion transporter family member 1B1/1B3/2B1 (Slco1b1 / 1b3 / 2b1)
Animal models are important tools for estimating drug disposition and the probability of drug-drug interactions in humans. Among the preclinical species, monkeys are the closest to human in terms of pharmacokinetic/pharmacodynamic characteristics due to our evolutionary kinship. Cynomolgus monkeys (Macaca fascicularis) are among the nonhuman primates most widely used in preclinical research.
Organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 are major uptake transporters that play important roles in drug disposition . The OATP family members are poorly conserved across more distantly related species such as humans, dogs and rodents . Cynomolgus monkey Oatps, however, show a high degree of amino acid sequence homology with their human orthologs. For cyOatp1b1, cyOatp1b3 and cyOatp1b2 the identities are 91.9%, 93.5% and 96.6%, respectively [3, 4]. Cynomolgus Oatps are expressed exclusively in the liver , and show higher protein levels compared to humans .
The substrate specificities and inhibition profiles of cyOatps are also similar to those of their human counterparts [3, 6], with some notable exceptions. Digoxin, for example, is a hOATP1B3-specific substrate , and whereas hOATP1B1, cyOatp1b1 and hOATP1B3 are most potently inhibited by rifampin, cyOatp1b3 is more sensitive to cyclosporin A than rifampin inhibition . Further, rifampin is less powerful at inhibiting cyOatp2b1-mediated rosuvastatin and atorvastatin uptake, but exhibits strong inhibition of cyOatp1b1- and cyOatp1b3-mediated rosuvastatin and atorvastatin uptake . Telmisartan, a known hOATP1B3-specific substrate, is a substrate of cyOATP1B3 as well as cyOATP2B1 .
Despite the overall similarities, differences between monkeys and humans exist in the dosing regimens, transporter expression levels, and mechanisms involved in drug clearance; hence, it is often challenging to directly compare hepatic transporter-mediated drug-drug interactions (DDIs) across the species . The few comparative studies conducted so far have come to contradictory conclusions. Chu et al. reported a lack of translation of atorvastatin-rifampicin DDI from cynomolgus monkeys to humans, which may indicate species differences in the rate-limiting elimination pathways . For example, hepatic and renal clearance of rosuvastatin in humans was estimated to account for 72% and 28% of total elimination, respectively [9, 10], whereas the renal clearance was significantly lower (<5%) in cynomolgus monkey . Other groups, however, have found that rifampicin-mediated DDIs were in a good agreement between cynomolgus monkeys and humans, as quantitative OATP1B DDI predictions could be made from in vitro IC50 values measured in monkey primary hepatocytes using rosuvastatin as a probe substrate following pre-incubation with rifampicin [11, 12].
Although further characterization of monkey transporters will be needed and differences in rate-limiting pathways between monkeys and humans must be taken into consideration, a growing body of data suggests that cynomolgus monkeys may serve as a model for predicting OATP-mediated DDIs in humans .
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