Short-lasting inhibition of hepatic uptake transporter OATP1B1 by tyrosine kinase inhibitor pazopanib.

Risk assessment of organic anion transporting polypeptide 1B1 (OATP1B1)-mediated drug-drug interactions (DDIs) is an integral part of drug development, but the difficult aspects in DDI prediction include complex mechanism of OATP1B1 inhibition. Pazopanib, an orally available tyrosine kinase inhibitor, exhibits OATP1B1 inhibition and clinically interacts with some OATP1B1 substrates, although quantitative analysis of DDI potential has not yet been performed. The purpose of the present study was to characterize the inhibitory effect of pazopanib on OATP1B1-mediated transport. Inhibition by pazopanib of OATP1B1-mediated uptake of two typical substrates, [3H]estrone-3-sulfate (E1S) and [3H]estradiol-17β-glucuronide, assessed in HEK293/OATP1B1 cells, was more obvious after preincubation with pazopanib compared with no preincubation. The reduction in IC50 values was 3-7 times greater and was comparable with the preincubation effect of another long-lasting inhibitor, cyclosporine A (CsA). Preincubation with pazopanib and CsA tended to similarly reduce Vmax and increase Km values of E1S. However, the reduced OATP1B1 activity by preincubation with pazopanib was more rapidly recovered than CsA. In addition, R value, which predicts the maximum increase in the AUC ratio of victim drugs, was calculated to be 1.09. These results suggest that pazopanib is preincubation-dependent but a short-lasting inhibitor against OATP1B1 with low potential of OATP1B1-mediated DDIs.