Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3 |
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| Authors: | Toshihiro Sato Hajime Ito Ayaka Hirata Takaaki Abe Nariyasu Mano |
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| Affiliation: | 1. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan,;2. Laboratory of Clinical Pharmaceutics &3. Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan,;4. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan,;5. Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan,;6. Division of Medical Science, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan, and;7. Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine, Tohoku University, Sendai, Japan;8. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan,;9. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan, |
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| Abstract: | 1.?The drug–drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs.2.?To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies. We examined the effects of the TKIs on uptake of typical substrates and fluvastatin via OATPs. IC50 and EC50 values of the TKIs were calculated.3.?OATP1B3- and OATP2B1-mediated crizotinib uptake and OATP2B1-mediated gefitinib uptake were observed. Gefitinib accelerated OATP1B3-mediated [3H]TCA uptake and inhibited OATP2B1-mediated [3H]E3S uptake. On the other hand, gefitinib inhibited OATP1B1- and OATP2B1-mediated fluvastatin uptake.4.?We provided basic information to estimate the DDI on OATPs caused by TKIs. The DDI on OATPs caused by gefitinib could occur in a normal clinical situation. And the uptake of crizotinib into the intrahepatocellular environment via OATPs may induce DDI and liver damage. We therefore emphasize the necessity of careful use of TKIs. |
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| Keywords: | Crizotinib drug–drug interaction gefitinib liver injury OATP tyrosine kinase inhibitor |
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