[HTML][HTML] Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro–in vivo correlations
British journal of cancer, 2014•nature.com
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 …
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 …
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.
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