Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.

Abstract

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 >or= .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.

• Authors: Erin R Gardner, Herman Burger, Ron H van Schaik, Allan T van Oosterom, Ernst A de Bruijn, Gunther Guetens, Hans Prenen, Floris A de Jong, Sharyn D Baker, Susan E Bates, William D Figg, Jaap Verweij, Alex Sparreboom, Kees Nooter
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 80 Issue 2 Pg. 192-201 (Aug 2006) ISSN: 0009-9236 [Print] United States
• PMID: 16890580 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Benzamides
• Carrier Proteins
• Isoenzymes
• Pharmaceutical Preparations
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Cytochrome P-450 Enzyme System
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-kit

Topics

• ATP-Binding Cassette Transporters (genetics)
• Adult
• Aged
• Aged, 80 and over
• Alleles
• Benzamides
• Biological Transport, Active
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cohort Studies
• Cytochrome P-450 Enzyme System (genetics)
• Female
• Gastrointestinal Neoplasms (genetics, metabolism)
• Gene Frequency
• Genotype
• Humans
• Imatinib Mesylate
• Isoenzymes (genetics)
• Male
• Middle Aged
• Pharmaceutical Preparations (metabolism)
• Phenotype
• Piperazines (pharmacokinetics)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-kit (genetics)
• Pyrimidines (pharmacokinetics)
• Stromal Cells (metabolism)