title: Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia.
abstract: This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with the SLCO1B3 334GG genotype (median value ± standard deviation, 9.5 ± 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 ± 3.1 L/hr; n = 15) (P = 0.019). Patients with the ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 ± 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 ± 2.7 L/hr; n = 27) (P = 0.035). In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia.
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamakawa
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: Chie
authors.initials: C
authors.lastname: Hirayama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D001549:Benzamides; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000235:genetics; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C073119:TAP1 protein, human; C400322:cytochrome P-450 CYP2C subfamily; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A