Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations.

Abstract:

BACKGROUND:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1. METHODS:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice. RESULTS:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics. CONCLUSION:These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters.

journal_name

Br J Cancer

authors

Hu S,Mathijssen RH,de Bruijn P,Baker SD,Sparreboom A

doi

10.1038/bjc.2013.811

subject

Has Abstract

pub_date

2014-02-18 00:00:00

pages

894-8

issue

4

eissn

0007-0920

issn

1532-1827

pii

bjc2013811

journal_volume

110

pub_type

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