Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

Abstract

Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by (31)P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses </=1000 mg/m(2), whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (+/-SD) CP elimination constants k(e) (h(-1)) were 0.109+/-0.025 in 44 CYP2C19*1/*1 subjects, 0.088+/-0.018 in 13 CYP2C19*1/*2, and 0.076+/-0.014 in three inactive CYP2C19*2/*2 carriers (P=0.009). At CP doses higher than 1000 mg/m(2), a significantly increase of elimination was observed (P=0.001), possibly due to CYP induction. Further studies should link these findings with the clinical outcome.