title: CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients.
abstract: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients.
  
  
  
  We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc).
  
  
  
  CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively).
  
  
  
  CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia. daniel.barratt@adelaide.edu.au.|Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia. daniel.barratt@adelaide.edu.au.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Barratt
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Cox
authors.affiliation: South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
authors.forename: David T
authors.initials: DT
authors.lastname: Yeung
authors.affiliation: South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: White
authors.affiliation: South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia.|Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.|Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017322:Clinical Trials, Phase II as Topic; D065727:Cytochrome P-450 CYP2C8 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D020794:Receptor Protein-Tyrosine Kinases