title: 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.affiliation: Clinical Pharmacology Research Core, SAIC-Frederick, Frederick, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.forename: Ron H
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Allan T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: Ernst A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: Gunther
authors.initials: G
authors.lastname: Guetens
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.forename: Floris A
authors.initials: FA
authors.lastname: de Jong
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Kees
authors.initials: K
authors.lastname: Nooter
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001549:Benzamides; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D010879:Piperazines / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000493:pharmacokinetics*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D002352:Carrier Proteins; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit