Members of the hepatic
cytochrome p450 superfamily(CYP)play an important role in the metabolism of many therapeutic drugs. There is a marked individual variability in the CYP-mediated
drug metabolism. One of the main factors of the CYP activities is a polymorphism of the CYP genes. Polymorphisms of the CYP genes contribute to the variation in the
drug-metabolic rate. The polymorphic nature of the CYP genes affects the individual
drug response and adverse reactions.
Cyclophosphamide(CPA)exerts its effect after biotransformation to 4-hydroxy-CPA by hepatic CYP. Several CYPs have been reported to mediate this reaction. Especially
CYP2B6 is thought to be the key
enzyme in the CPA metabolism.
CYP2B6 is highly polymorphic, and it has been reported that the genetic backgrounds of
CYP2B6 in Japanese and Caucasians are different.
CYP2B6*6, which is a relatively common allele in the Japanese population, affects the gene expression and activities of
CYP2B6 in vitro. The homozygote of
CYP2B6*6 patients with
malignant lymphoma and
breast cancer treated with CPA showed higher clearance and shorter half-life of plasma CPA. In addition, homozygous
CYP2B6*5 patients with proliferative
lupus nephritis had a significantly higher probability of reaching
end-stage renal disease by pulse CPA treatment. Other gene polymorphisms of
CYP2B6 also affect the CPA metabolism in vitro. However, the current knowledge of
CYP2B6 polymorphism is not sufficient to predict its efficacy and safety for the individual patient in CPA
therapy. Further studies are needed for clinical use.