Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia.
Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P=0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P=0.015). Moreover, previous studies have shown that the ABCG2 421C>A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C>A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.
Takahashi
Naoto
N
Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Miura
Masatomo
M
Scott
Stuart A
SA
Kagaya
Hideaki
H
Kameoka
Yoshihiro
Y
Tagawa
Hiroyuki
H
Saitoh
Hirobumi
H
Fujishima
Naohito
N
Yoshioka
Tomoko
T
Hirokawa
Makoto
M
Sawada
Kenichi
K
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D011505:Protein-Tyrosine Kinases