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Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes

  • Pharmacokinetics and Disposition
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Abstract

Several-fold differences have been observed among patients in the biotransformation of cyclophosphamide. The aim of this study was to investigate the contribution of CYP2C9 and CYP2C19 and their polymorphisms to the variability of cyclophosphamide activation. The formation of 4-hydroxycyclophosphamide was studied in microsomes from a total of 32 different genotyped human livers, as well as in yeast microsomes expressing different genetic variants of CYP2C9 and CYP2C19. The kinetic data obtained in the yeast system revealed that the intrinsic clearance (Vmax/Km) of cyclophosphamide by CYP2C9.2 and CYP2C9.3 samples was approximately threefold lower than that by CYP2C9.1. However, in liver microsomes, there were no statistically significant differences in the intrinsic clearance of 4-hydroxycyclophosphamide formation between the group of seven CYP2C9*1/*1 livers and the remaining nine with one or two variant CYP2C9 alleles (P>0.7). We found a statistically significant correlation (r s=0.65, P=0.003) between 4-hydroxylation of cyclophosphamide and 5′-hydroxylation of R-omeprazole, a measure of CYP2C19 activity in human liver microsomes (n=19). No correlation was found between 4-hydroxylation of cyclophosphamide and the formation rate of hydroxycelecoxib, mainly catalysed by CYP2C9 (r s=0.17, P=0.55, n=32). In conclusion, based on the correlation with the formation of R-5′-hydroxyomeprazole, CYP2C19 may partly contribute to the bioactivation of cyclophosphamide in human liver microsomes, while the role of CYP2C9 appears minor.

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Acknowledgements

The study was granted by Swedish Children Cancer Foundation (PROJ01/59), Medical Research Council (3902, 4496 and 5949), Stockholm Cancer Foundation (02:119), King Gustav V Jubilee Foundation and Karolinska Institutet.

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  1. Ümit Yasar

    Present address: Hacettepe University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey

Authors and Affiliations

  1. Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet at Huddinge University Hospital, 14186 , Stockholm, Sweden

    Laimonas Griskevicius, Ümit Yasar, Mia Sandberg, Erik Eliasson & Gunnel Tybring

  2. Department of Medicine, Division of Haematology, Laboratory of Hematology, KFC Novum, Karolinska Institutet, Huddinge University Hospital, 14186 , Stockholm, Sweden

    Laimonas Griskevicius & Moustapha Hassan

  3. Institute of Environmental Medicine, Division of Molecular Toxicology, Karolinska Institutet, 17177 , Stockholm, Sweden

    Mats Hidestrand

  4. Department of Medical Sciences, Clinical Pharmacology, University Hospital, 75185, Uppsala, Sweden

    Marja-Liisa Dahl

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  1. Laimonas Griskevicius
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Correspondence to Moustapha Hassan.

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Griskevicius, L., Yasar, Ü., Sandberg, M. et al. Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Eur J Clin Pharmacol 59, 103–109 (2003). https://doi.org/10.1007/s00228-003-0590-6

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  • DOI: https://doi.org/10.1007/s00228-003-0590-6

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