Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

The potential of tyrosine kinase inhibitors (TKIs) interacting with other therapeutics through hepatic uptake transporter inhibition has not been fully delineated in drug-drug interactions (DDIs). This study was designed to estimate the half-maximal inhibitory concentration (IC50) values of five small-molecule TKIs (pazopanib, nilotinib, vandetanib, canertinib and erlotinib) interacting with organic anion-transporting polypeptides (OATPs): OATP-1B1 and -1B3.

Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs.

The IC50 values of TKIs and rifampicin (positive control) were determined by concentration-dependent inhibition of TKIs on cellular accumulation of radiolabeled probe substrates [3H]estrone sulfate and [3H]cholecystokinin octapeptide. Chinese hamster ovary cells transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins, respectively, were utilized to carry out these studies.

Pazopanib and nilotinib show inhibitory activity on OATP-1B1 transporter protein. IC50 values for rifampicin, pazopanib and nilotinib were 10.46±1.15, 3.89±1.21 and 2.78±1.13 μM, respectively, for OATP-1B1 transporter. Vandetanib, canertinib and erlotinib did not exhibit any inhibitory potency toward OATP-1B1 transporter protein. Only vandetanib expressed inhibitory potential toward OATP-1B3 transporter protein out of the five selected TKIs. IC50 values for rifampicin and vandetanib for OATP-1B3 transporter inhibition were 3.67±1.20 and 18.13±1.21 μM, respectively. No significant inhibition in the presence of increasing concentrations of pazopanib, nilotinib, canertinib and erlotinib were observed for OATP-1B3 transporter. Conclusions: Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs.