title: Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide.
abstract: OBJECTIVE
  The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4-hydroxycyclophosphamide.
  
  
  METHODS
  A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4-hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling.
  
  
  RESULTS
  The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-hydroxycyclophosphamide could be demonstrated.
  
  
  CONCLUSIONS
  This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. Corine.Ekhart@slz.nl
authors.forename: Corine
authors.initials: C
authors.lastname: Ekhart
authors.forename: Valerie D
authors.initials: VD
authors.lastname: Doodeman
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Paul H M
authors.initials: PH
authors.lastname: Smits
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000293:Adolescent; D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D050697:Retinal Dehydrogenase
chemical_list: D017931:DNA Primers; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000080924:Aldehyde Dehydrogenase 1 Family; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D010089:Oxidoreductases, N-Demethylating; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase