The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The prodrug cyclophosphamide requires bioactivation by liver CYP enzymes. • Controversy exists about which CYP isoforms are important in the in vitro bioactivation of this drug. • Recent clinical studies have highlighted a role for either CYP2C19 or CYP2B6...

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Published in:British journal of clinical pharmacology 2010-12, Vol.70 (6), p.844-853
Main Authors: Helsby, Nuala A., Hui, Chung‐Yee, Goldthorpe, Michael A., Coller, Janet K., Soh, May Ching, Gow, Peter J., De Zoysa, Janak Z., Tingle, Malcolm D.
Format: Article
Language:English
Subjects:
Adult
Aged
Alleles
Aryl Hydrocarbon Hydroxylases - genetics
Aryl Hydrocarbon Hydroxylases - metabolism
Cyclophosphamide
Cyclophosphamide - pharmacokinetics
CYP2B6
CYP2C19
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP2C19
Female
Genotype
Humans
Immunosuppressive Agents - pharmacokinetics
lupus
Lupus Nephritis - blood
Lupus Nephritis - genetics
Male
Microsomes, Liver - metabolism
Middle Aged
Oxidoreductases, N-Demethylating - genetics
Oxidoreductases, N-Demethylating - metabolism
Pharmacogenetics
Tissue Banks
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Summary:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The prodrug cyclophosphamide requires bioactivation by liver CYP enzymes. • Controversy exists about which CYP isoforms are important in the in vitro bioactivation of this drug. • Recent clinical studies have highlighted a role for either CYP2C19 or CYP2B6 in the therapeutic response to cyclophosphamide in lupus patients. • However, the role of these isoforms in the bioactivation of cyclophosphamide in lupus patients has not been previously demonstrated. WHAT THIS STUDY ADDS • Low bioactivation of cyclophosphamide by human liver appears to be dependent on a combination of both CYP2C19 and CYP2B6 loss of function variants. • In a preliminary study of lupus patients poor bioactivation of cyclophosphamide was also observed in those individuals who had at least one loss of function allele at either CYP2C19 or CYP2B6. AIMS The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODS We used a combined in vitro–in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4‐hydroxy cyclophosphamide (4‐OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n= 14) and in patients receiving the drug for treatment of lupus nephritis (n= 16) RESULTS In livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both Vmax (P= 0.028) and CLint (P= 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had ≥1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P= 0.0316) lower bioactivation of cyclophosphamide. The mean 4‐OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes. CONCLUSIONS The presence of ≥1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.
ISSN:0306-5251
1365-2125
DOI:10.1111/j.1365-2125.2010.03789.x