title: Association of SLCO1B3 polymorphism with intracellular accumulation of imatinib in leukocytes in patients with chronic myeloid leukemia.
abstract: 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=0.0188). Plasma concentrations were similar in both SLCO1B3 genotypes (p=0.860), thereby resulting in the intracellular to plasma concentration ratio being higher in patients with SLCO1B3 334TT than those with 334 TG/GG (p=0.0502). These results suggested that the SLCO1B3 334T>G polymorphism could have a significant impact on the intracellular concentration of imatinib in leukocytes as a promising biomarker for personalized treatment of CML patients.
authors.affiliation: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Nambu
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Reiko
authors.initials: R
authors.lastname: Nakashima
authors.forename: Misato
authors.initials: M
authors.lastname: Yuki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001549:Benzamides; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D007962:Leukocytes / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000378:metabolism* / Q000627:therapeutic use; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D029362:Organic Anion Transporters, Sodium-Independent; D010879:Piperazines; D011743:Pyrimidines; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000068877:Imatinib Mesylate