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Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

The Pharmacogenomics Journal volume 5, pages 365–373 (2005)Cite this article

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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Authors and Affiliations

  1. Institute of Pharmacology, Ernst Moritz Arndt University Greifswald, Germany

    R Timm & I Cascorbi

  2. Department of Clinical Pharmacology, Georg August University Göttingen, Germany

    R Kaiser

  3. Institute of Clinical Pharmacology, pharmazentrum frankfurt, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany

    J Lötsch

  4. Department of Oncology and Hematology, Campus Charité Mitte, Charité University Medicine Berlin, Berlin, Germany

    U Heider & O Sezer

  5. Institute of Chemistry and Biochemistry, Ernst Moritz Arndt University Greifswald, Germany

    K Weisz

  6. Department of Hematology and Oncology, Ernst Moritz Arndt University Greifswald, Germany

    M Montemurro

  7. Institute of Clinical Pharmacology, Campus Charité Mitte, Charité University Medicine, Berlin

    I Roots

  8. Institute of Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany

    I Cascorbi

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  1. R Timm
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Correspondence to I Cascorbi.

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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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