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Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib
Author(s) -
Gardner Erin R.,
Burger Herman,
Schaik Ron H.,
Oosterom Allan T.,
Bruijn Ernst A.,
Guetens Gunther,
Prenen Hans,
Jong Floris A.,
Baker Sharyn D.,
Bates Susan E.,
Figg William D.,
Verweij Jaap,
Sparreboom Alex,
Nooter Kees
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.05.003
Subject(s) - pharmacokinetics , pharmacology , imatinib , abcg2 , genotype , biology , cyp3a4 , atp binding cassette transporter , microbiology and biotechnology , transporter , cytochrome p450 , genetics , cancer research , enzyme , gene , myeloid leukemia , biochemistry
Objective Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate‐binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. Methods Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild‐type ABCG2 and an ABCG2 Q141K clone. Steady‐state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism‐based techniques. Results Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild‐type ABCG2 ( P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild‐type sequence ( P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple‐variant genotypes ( P ≥ .230), possibly because of the low allele frequencies. Conclusions This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib. Clinical Pharmacology & Therapeutics (2006) 80 , 192–201; doi: 10.1016/j.clpt.2006.05.003