Preclinical/Animal Transporters

Oatp1b3 -cynomolgus monkey

Oatp1b1/1b3/2b1 (organic anion transporting polypeptide 1b1/1b3/2b1), cynomolgus monkey

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. The use of cynomolgus monkey (Macaca fascicularis) has increased significantly in the past few years.
Organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 are major uptake transporters that play an important role in drug disposition [1]. The OATP family members are poorly conserved across more distantly related species such as humans, dogs and rodents [2]. Cynomolgus monkey Oatps, however, show a high degree of amino acid sequence homology with their human orthologs. In the case of 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 [4], and show higher protein levels as compared with humans [5].
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 [4], and whereas hOATP1B1, cyOatp1b1 and hOATP1B3 are most potently inhibited by rifampin, cyOatp1b3 is more sensitive to cyclosporin A than rifampin inhibition [3]. 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 [7]. Lack of translation of atorvastatin-rifampin DDI from cynomolgus monkeys to humans indicates species differences in the rate-limiting elimination pathways [7]. In humans, hepatic and renal clearance of rosuvastatin are estimated to account for 72% and 28% of total elimination [8, 9], whereas the renal clearance was significantly lower (<5%) [7] in cynomolgus monkey.
Although further characterization of monkey transporters will be needed and differences in rate-limiting pathways betweeen monkeys and humans must be taken into consideration, these features suggest that cynomolgus monkeys may serve as a model for predicting OATP-mediated drug-drug interactions (DDIs) in humans [7].

 

References

1.    Niemi, M., M.K. Pasanen, and P.J. Neuvonen, Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev, 2011. 63(1): p. 157-81.
2.    Chu, X., K. Bleasby, and R. Evers, Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol, 2013. 9(3): p. 237-52.
3.    Shen, H., et al., 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. J Pharmacol Exp Ther, 2013. 344(3): p. 673-85.
4.    White, E.P., et al., Cloning and characterization of rhesus monkey and cynomolgus monkey organic anion transporting polypeptide 1b3, and comparison of their substrate selectivity with human OATP1B3. Drug Metab Rev, 2006. 38(Suppl 2): p. 232-3.
5.    Wang, L., et al., Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos, 2015. 43(3): p. 367-74.
6.    Maeda, K. and Y. Sugiyama. Comparison of the function of transporters involved in the hepatic and renal uptake of drugs between monkeys and humans. in The 130th Annual Meeting of the Pharmaceutical Society of Japan. 2010. Okayama, Japan.
7.    Chu, X., et al., Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans. Drug Metab Dispos, 2015. 43(6): p. 851-63.
8.    Martin, P.D., et al., Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther, 2003. 25(11): p. 2822-35.
9.    Yoshida, K., K. Maeda, and Y. Sugiyama, Transporter-mediated drug--drug interactions involving OATP substrates: predictions based on in vitro inhibition studies. Clin Pharmacol Ther, 2012. 91(6): p. 1053-64.

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