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Pharmacokinetic Impact of SLCO1A2 Polymorphisms on Imatinib Disposition in Patients With Chronic Myeloid Leukemia
Author(s) -
Yamakawa Y,
Hamada A,
Shuto T,
Yuki M,
Uchida T,
Kai H,
Kawaguchi T,
Saito H
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.102
Subject(s) - imatinib , myeloid leukemia , disposition , pharmacokinetics , medicine , chronic myelogenous leukemia , pharmacology , oncology , leukemia , psychology , social psychology
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. Clinical Pharmacology & Therapeutics (2011) 90 1, 157–163. doi: 10.1038/clpt.2011.102