Serious haematological toxicity of cyclophosphamide in relation to CYP2B6, GSTA1 and GSTP1 polymorphisms.

摘要

Cyclophosphamide (CPA) is widely used as an anticancer and immunosuppressive agent in various indications, and the dosage given may vary considerably depending on the disease treated. A recent review has described the pharmacokinetics of CPA, a prodrug of which 70-80% of the administered dose is activated by cytochrome P450 (CYP) to the active alkylating species 4-hydroxycyclophosphamide (4OH-CPA). Several CYPs are responsible for CPA activation, mainly CYP2B6 and, secondarily, CYP2C9, CYP2C19 and CYP3A4/5 (Figure 1) . Systemic exposure to cyclophosphamide metabolites after fixed doses of cyclophosphamide may vary by up to 10-fold between patients . Genetic variants of CYPs involved in CPA metabolism may contribute to its pharma-cokinetic variability and genetic polymorphisms of glu-tathione S-transferases may influence its toxicity.