The most important OATP family member expressed in the human liver is OATP1B1, responsible for hepatic uptake and elimination of a wide range of endogenous compounds and drugs. Species differences in drug transporters with regards to tissue distribution, expression levels and substrate specificity can be problematic for interspecies extrapolation of drug pharmacokinetics and DDI potential.
In order to understand potential differences in preclinical species hepatic uptake, Cyprotex has validated substrate identification and inhibition assays utilising in vitro test systems for each of the major hepatic Oatp transporters of the predominant preclinical species; rat Oatp1b2, dog Oatp1b4 and cynomolgus monkey Oatp1b1.
These in vitro systems may be useful in the understanding of whether a molecule is a substrate of an active uptake transporter in the livers of preclinical species. This may assist in the interpretation of any unexpected in vivo tissue exposure data, for example liver accumulation in which the tissue concentration of a molecule far exceeds that in plasma. Additionally, it may also help towards understanding an underprediction of in vivo hepatic clearance in the preclinical species when scaled from in vitro microsomal data.
The validation of these preclinical species cell lines may also enable better interspecies extrapolation of transporter-mediated drug disposition and elimination. Recent publications suggest cynomolgus monkey could be a preclinical in vivo model used to perform Oatp1b1 pharmacokinetic DDI studies for a molecule on the back of in vitro human OATP1B1 IC50 data1. If such a model was implemented by industry then in conjunction, it would also be beneficial to understand the inhibitory potential of the molecule against cynomolgus monkey Oatp1b1 in order to make the inhibition data more relevant to the in vivo DDI study, and its interpretation.
1 Ufuk A et al., (2018) In Vitro-In Vivo Extrapolation of OATP1B-Mediated Drug-Drug Interactions in Cynomolgus Monkey. J Pharmacol Exp Ther 365(3): 688-699