Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide.

ABSTRACT:

Purpose

Many tyrosine kinase inhibitors (TKI) undergo extensive hepatic metabolism, but mechanisms of their hepatocellular uptake remain poorly understood. We hypothesized that liver uptake of TKIs is mediated by the solute carriers OATP1B1 and OATP1B3.

Experimental design

Transport of crizotinib, dasatinib, gefitinib, imatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib was studied in vitro using artificial membranes (PAMPA) and HEK293 cell lines stably transfected with OATP1B1, OATP1B3, or the ortholog mouse transporter, Oatp1b2. Pharmacokinetic studies were conducted with Oatp1b2-knockout mice and humanized OATP1B1- or OATP1B3-transgenic mice.

Results

All 10 TKIs were identified as substrates of OATP1B1, OATP1B3, or both. Transport of s

SUBMITTER: Zimmerman EI 

PROVIDER: S-EPMC3602278 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature