Erlotinib-A substrate and inhibitor of OATP2B1: pharmacokinetics and CYP3A-mediated metabolism in rSlco2b1-/- and SLCO2B1+/+ rats.

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The tyrosine kinase inhibitor erlotinib is recognized as a substrate of cytochrome P450 enzymes and drug transporters. Indeed, erlotinib's extensive metabolism to the active metabolite OSI-420 (desmethyl erlotinib) mainly involves CYP3A enzymes. Additionally, erlotinib is assumed to interact with the organic anion transporting polypeptide (OATP)2B1. In this study, we aimed to investigate the role of human OATP2B1 in erlotinib's metabolism through invitro and invivo experiments. Using Madin-Darby canine kidney cells expressing human OATP2B1 for competitive counterflow experiments, we confirmed erlotinib as inhibitor and substrate of the transporter. Moreover, invitro transport experiments revealed higher cellular accumulation of erlotinib at pH 5.5 than that at pH 7.4. Pharmacokinetic evaluation of orally administered erlotinib in male SLCO2B1+/+ and rSlco2b1-/- rats revealed that the human OATP2B1 does not significantly alter serum levels of erlotinib or its main metabolite OSI-420, although we observed a longer mean residence time of the metabolite in humanized rats. Although there was no difference in the OSI-420:erlotinib ratio over time in SLCO2B1+/+ and rSlco2b1-/- rats, we assessed the role of CYP3A1 and CYP3A2 in the metabolism of erlotinib. Invitro experiments showed a contribution of both enzymes to the formation of OSI-420. For CYP3A1, we found significantly higher expression in liver microsomes of male SLCO2B1+/+ rats, while the knockout genotype showed significantly higher levels of CYP3A2. However, these differences did not affect the systemic exposure of erlotinib or OSI-420 in the rats. Our findings provide further insight into the role of OATP2B1 in the disposition of orally administered erlotinib. SIGNIFICANCE STATEMENT: This study confirms that erlotinib is a substrate of the human organic anion transporting polypeptide 2B1 transporter invitro. Invivo experiments in rat models, however, showed no significant impact of organic anion transporting polypeptide 2B1 on the systemic exposure of erlotinib or its metabolite, OSI-420. Despite variations in CYP3A enzyme expression in SLCO2B1+/+ rats, the OSI-420:erlotinib ratio remained unchanged. Although SLCO2B1+/+ rats exhibited a longer mean residence time for OSI-420, this did not significantly alter overall exposure in orally treated animals.