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.

Intracellular concentration of imatinib in leukemic cells is thought to affect the clinical efficacy of this drug in patients with chronic myeloid leukemia (CML); however, there is no report that directly indicates the relationship between intracellular concentration and clinical outcome and/or, plasma concentration. In addition, the impacts of genetic variations of drug transporters, which mediate leukocyte concentration of imatinib, are unknown. In the present study, we investigated the correlation between intracellular imatinib concentrations in leukocytes, plasma imatinib levels, and genotypes of drug transporters, including ATP binding cassette B1 (ABCB), ABCG2, solute carrier 22A1 (SLC22A1), solute carrier organic anion transporter family members 1B1 (SLCO1B1) and SLCO1B3. The imatinib levels in leukocytes were determined using HPLC in 15 patients with chronic phase CML. No significant correlation between intracellular and plasma concentrations of imatinib was observed. The intracellular concentration was comparable in both patients with or without complete cytogenetic response. The intracellular imatinib concentration was significantly higher in patients with SLCO1B3 334TT than in those with 334TG/GG ( p‫؍‬ ‫.)8810.0؍‬ Plasma concentrations were similar in both SLCO1B3 genotypes (p‫؍‬ ‫,)068.0؍‬ thereby resulting in the intracellular to plasma concentration ratio being higher in patients with SLCO1B3 334TT than those with 334 TG/GG ( p‫؍‬ ‫.)2050.0؍‬ These results suggested that the SLCO1B3 334TϾ ϾG polymorphism could have a significant impact on the intracellular concentration of imatinib in leukocytes as a promising biomarker for personalized treatment of CML patients.

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Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clinical response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7-to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition experiments in K562 cells, and examination of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/ IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clinical response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gpoverexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.