The combined impact ofCYP2C19andCYP2B6pharmacogenetics 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 thein vitrobioactivation of this drug. • Recent clinical studies have highlighted a role for eitherCYP2C19orCYP2B6in 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 bothCYP2C19andCYP2B6loss 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 eitherCYP2C19orCYP2B6. AIMS The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for eitherCYP2C19orCYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODS We used a combinedin vitro–in vivoapproach 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 knownCYP2C19andCYP2B6genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamidein vitro. The presence of at least one loss of function (LoF) allele at eitherCYP2C19orCYP2B6resulted in a significant decrease in bothVmax(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 eitherCYP2C19orCYP2B6also 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 eitherCYP2B6orCYP2C19appeared to result in decreased bioactivation of cyclophosphamide bothin vitroand in patients. Further clinical studies to confirm this relationship are warranted.