A1 Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus

Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus

“…Pharmacogenetic studies regarding ovarian toxicity of cyclophosphamide in other Asian patients with SLE had shown somewhat similar results as our study, i.e. studies by Takada et al [12] and Singh et al [13] found lower risk of developing ovarian toxicity in homozygous/ heterozygous variant CYP2C19*2 allele compared with wild CYP2C19*1 allele although there were differences in dosages and routes of administration. The average cumulative dosages of cyclophosphamide for these two studies were only 17.4 and 9.3 g whereas the cumulative dosage for our study was as high as 23.8 g. Routes of administration for cyclophosphamide were also different; the two former studies used intravenous administration only, whereas our study used both oral and intravenous administration.…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…However, contradictory or negative results were presented in other studies of the association between CYP2B6 and pharmacokinetics/clinical outcome [88][89][90][91] . Notably, remarkable interindividual variety in the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide had been reported in Han Chinese in South China [91] .…”

Which CYP2B6 Variants Have Functional Consequences for Cyclophosphamide Bioactivation?: TABLE 1

“…Consistent with decreased in vitro bioactivation of cyclophosphamide by CYP2B6.5, there is a lack of therapeutic response to cyclophosphamide in individuals homozygous for CYP2B6*5 (Takada et al, 2004;Black et al, 2012). The cytotoxic agent cyclophosphamide is a prodrug, and CYP2B6*5 has also been significantly associated with a decrease in adverse events (Takada et al, 2004;Singh et al, 2007;Black et al, 2012). However, a higher incidence of dose delay (implying increased bioactivation to the cytotoxin) is associated with CYP2B6*5 in patients treated with a combination of cyclophosphamide and doxorubicin (Bray et al, 2010).…”

“…There is evidence that both CYP2B6 and CYP2C19 are important in the biotransformation and activation of this prodrug in vitro (Chang et al, 1993(Chang et al, , 1997Huang et al, 2000;Griskevicius et al, 2003;Xie et al, 2003;Chen et al, 2004) and in vivo (Timm et al, 2005;Xie et al, 2006;Nakajima et al, 2007;Helsby et al, 2010;Afsar et al, 2011). However, whereas there is some evidence to support altered therapeutic response and/or toxicity in patients who have single nucleotide polymorphisms (SNP) variants of either of these P450 enzymes (Takada et al, 2004;Elmaagacli et al, 2007;Singh et al, 2007;Tran et al, 2008;Bray et al, 2010;Melanson et al, 2010;Afsar et al, 2011;Black et al, 2012), not all studies confirm this effect (Petros et al, 2005;Ekhart et al, 2008;Low et al, 2009;Yao et al, 2010;Winoto et al, 2011). This lack of consistency in the published literature may in part relate to invalid assumptions regarding the functional changes associated with each CYP2B6 genotype and hence misclassification of metabolizer categories.…”