Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia
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The purpose of this study was to explore the role of the organic-anion transporting polypeptide (OATP) 1A2 that 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 chronic myeloid leukemia (CML) patients. 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, the human intestinal cell line Caco-2, and the CML cell line K562 cells. Linkage disequilibrium was found between the SLCO1A2 -1105G>A and -1032G>A genotypes in 34 CML patients and 100 healthy subjects. Imatinib clearance of 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.
- Clinical Pharmacology and Therapeutics
Clinical Pharmacology and Therapeutics 90(1), 157-163, 2011-07-01
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