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 31P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses ⩽1000 mg/m2, whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (±SD) CP elimination constants ke (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/m2, 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.
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Acknowledgements
This work was supported by a grant of the German Federal Ministry of Education and Research 01 GG 9845/5 to IC and IR We thank Baxter Oncology GmbH for providing us with CP and ifosphamide. The excellent technical assistance of Ingrid Geissler, Maria Purwanto and Zhou Xiao is gratefully acknowledged.
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Timm, R., Kaiser, R., Lötsch, J. et al. Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19. Pharmacogenomics J 5, 365–373 (2005). https://doi.org/10.1038/sj.tpj.6500330
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DOI: https://doi.org/10.1038/sj.tpj.6500330
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