Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients

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Authors: S. J. Seong ; M. Lim ; S. K. Sohn ; J. H. Moon ; S.-J. Oh ; B. S. Kim ; H. M. Ryoo ; J. S. Chung ; Y. D. Joo ; S. M. Bang ; C. W. Jung ; D. H. Kim ; S. Y. Park ; S. S. Yoon ; I. Kim ; H. G. Lee ; J. H. Won ; Y. H. Min ; J. W. Cheong ; J. S. Park ; K. S. Eom ; M. S. Hyun ; M. K. Kim ; H. Kim ; M. R. Park ; J. Park ; C. S. Kim ; H. J. Kim ; Y. K. Kim ; E. K. Park ; D. Y. Zang ; D. Y. Jo ; H. W. Lee ; Y.-R. Yoon

MeSH: ATP Binding Cassette Transporter, Sub-Family B ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette, Sub-Family B, Member 1/genetics ; Adolescent ; Adult ; Aged ; Antineoplastic Agents/pharmacokinetics* ; Aryl Hydrocarbon Hydroxylases/genetics ; Benzamides/pharmacokinetics* ; Female ; Gene Frequency ; Genotype ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Male ; Middle Aged ; Neoplasm Proteins/genetics ; Organic Cation Transport Proteins/genetics ; Organic Cation Transporter 2 ; Piperazines/pharmacokinetics* ; Polymorphism, Single Nucleotide* ; Pyrimidines/pharmacokinetics* ; Treatment Outcome ; Young Adult

Keywords: ABCG ; chronic myeloid leukemia ; clinical response ; imatinib trough concentration

Abstract: BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML).

PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy.

RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR.

CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.