Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

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.