title: Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia.
abstract: The purpose of this study was to explore the role of the organic anion-transporting polypeptide (OATP) 1A2, which is encoded by SLCO1A2, in the cellular uptake of the Bcr-Abl tyrosine kinase inhibitor imatinib, and the relationship between SLCO1A2 polymorphisms and the pharmacokinetics of imatinib in patients with chronic myeloid leukemia (CML). Imatinib uptake was significantly enhanced in OATP1A2-transfected human embryonic kidney (HEK) 293 cells (P = 0.002). Naringin, an OATP1A2 inhibitor, decreased the transport of imatinib in OATP1A2-transfected HEK293 cells, the human intestinal cell line Caco-2, and K562 CML cells. Linkage disequilibrium was found between the SLCO1A2 -1105G>A and -1032G>A genotypes in 34 CML patients and 100 healthy subjects. Imatinib clearance in CML patients was influenced by the SLCO1A2 -1105G>A/-1032G>A genotype (P = 0.075) and the SLCO1A2 -361GG genotype (P = 0.005). These findings suggest that imatinib is transported into cells by OATP1A2, and that SLCO1A2 polymorphisms significantly affect imatinib pharmacokinetics.
authors.affiliation: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: A
authors.initials: A
authors.lastname: Hamada
authors.forename: T
authors.initials: T
authors.lastname: Shuto
authors.forename: M
authors.initials: M
authors.lastname: Yuki
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.forename: H
authors.initials: H
authors.lastname: Kai
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: H
authors.initials: H
authors.lastname: Saito
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D018938:Caco-2 Cells; D004247:DNA / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology; D005838:Genotype; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001549:Benzamides; D044950:Flavanones; D027361:Organic Anion Transporters; D010879:Piperazines; D011743:Pyrimidines; C512988:SLCO1A2 protein, human; D000068877:Imatinib Mesylate; D004247:DNA; C005274:naringin