title: Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3.
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. IC50and EC50values 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.
authors.affiliation: a Department of Pharmaceutical Sciences , Tohoku University Hospital , Sendai , Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: b Laboratory of Clinical Pharmaceutics & Therapeutics , Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University , Sapporo , Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ito
authors.affiliation: c Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai , Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Hirata
authors.affiliation: d Division of Nephrology , Endocrinology, and Vascular Medicine, Graduate School of Medicine, Tohoku University , Sendai , Japan.|e Division of Medical Science , Graduate School of Biomedical Engineering, Tohoku University , Sendai , Japan , and.|f Department of Clinical Biology and Hormonal Regulation , Graduate School of Medicine, Tohoku University , Sendai , Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
authors.affiliation: a Department of Pharmaceutical Sciences , Tohoku University Hospital , Sendai , Japan.|c Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai , Japan.
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
authors.affiliation: a Department of Pharmaceutical Sciences , Tohoku University Hospital , Sendai , Japan.|c Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai , Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
mesh_terms: D000077547:Crizotinib; D004347:Drug Interactions; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011799:Quinazolines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077547:Crizotinib; D000077156:Gefitinib
keywords: Crizotinib; OATP; drug–drug interaction; gefitinib; liver injury; tyrosine kinase inhibitor