Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and

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Pharmacogenet Genomics. 2008 Jun;18(6):515-23.
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.

Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD.
 
Department
of Pharmacy and Pharmacology, The Netherlands Cancer
Institute/Slotervaart Hospital, Amsterdam, The Netherlands.

 
PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.
CONCLUSION: 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.