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Review
. 2019 Sep;85(9):1925-1934.
doi: 10.1111/bcp.14031. Epub 2019 Jul 22.

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

N A Helsby  1 , M Yong  1 , M van Kan  1 , J R de Zoysa  2   3 , K E Burns  1
Affiliations
Review

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

N A Helsby et al. Br J Clin Pharmacol. 2019 Sep.

Abstract

Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene-gene interactions to confirm these findings and may allow personalised treatment regimens.

Keywords: chemotherapy; cytochrome P450 enzymes; genetic polymorphism; genetics and pharmacogenetics; oncology.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The complex activation and inactivation pathways of cyclophosphamide. These pathways involve enzymes such as the cytochrome P450 (CYP) and aldehyde dehydrogenase (ALDH). Only the major metabolic products are shown, with the inactivation pathways shown in grey. The major route of biotransformation of cyclophosphamide is via 4‐hydroxylation6 whereas CYP3A4 catalysed N‐dechloroethylation is a minor route contributing on average 19% of metabolic clearance7
See this image and copyright information in PMC

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