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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Transport / drug effects
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Docetaxel
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Drug Interactions
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HEK293 Cells
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Liver / drug effects
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Liver / metabolism
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Liver-Specific Organic Anion Transporter 1
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Mice
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Mice, Knockout
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Organic Anion Transporters / antagonists & inhibitors*
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Organic Anion Transporters / genetics
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Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors
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Organic Anion Transporters, Sodium-Independent / genetics
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Phenylurea Compounds / pharmacology
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Sorafenib
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Taxoids / pharmacokinetics
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Taxoids / pharmacology*
Substances
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Liver-Specific Organic Anion Transporter 1
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Organic Anion Transporters
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Organic Anion Transporters, Sodium-Independent
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Phenylurea Compounds
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Protein Kinase Inhibitors
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SLCO1B1 protein, human
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Slco1b2 protein, mouse
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Taxoids
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Docetaxel
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Niacinamide
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Sorafenib
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Protein-Tyrosine Kinases