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The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation
Author(s) -
Helsby Nuala A.,
Hui ChungYee,
Goldthorpe Michael A.,
Coller Janet K.,
Soh May Ching,
Gow Peter J.,
De Zoysa Janak Z.,
Tingle Malcolm D.
Publication year - 2010
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2010.03789.x
Subject(s) - cyp2c19 , cyclophosphamide , pharmacology , pharmacogenetics , cyp2b6 , prodrug , medicine , chemistry , cytochrome p450 , genotype , chemotherapy , cyp3a4 , biochemistry , metabolism , gene
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 V max ( P = 0.028) and CL int ( 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.