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Br J Cancer. 2014 Feb 18;110(4):894-8. doi: 10.1038/bjc.2013.811. Epub 2014 Jan 7.

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

Author information

1
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA [2] Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.

PMID:
24398510
PMCID:
PMC3929889
DOI:
10.1038/bjc.2013.811
[Indexed for MEDLINE]
Free PMC Article

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