The Inhibitory Effects of Anticancer Drugs Cyclophosphamide, Etoposide and Vincristine on CYP2C19-mediated S-mephenytoin 4'-hydroxylation in Human Liver Microsomes

抄録

Cyclophosphamide, etoposide and vincristine are widely used for cancer chemotherapy and are frequently prescribed concurrently. Although a high possibility of drug-drug interactions during cancer chemotherapy is predicted, little information is available concerning the effects of these anticancer drugs on cytochrome P450 (CYP), the enzyme that metabolizes a wide variety of drugs. This study was designed to evaluate the inhibitory effect of cyclophosphamide, etoposide and vincristine on CYP2C 19-mediated drug metabolism individually and when used in combinations of two or three of these drugs in vitro. Human liver microsomal fractions were employed as an enzyme source and S-mephenytoin was used as a probe for the estimation of CYP2C 19-mediated drug metabolism. Each of these drugs inhibited S-mephenytoin 4'-hydroxylation competitively with Ki values of 1800, 120 and 90 pM, respectively. The inhibitory effects of combinations of these drugs on CYP2C 19 were investigated using concentrations of each drug that inhibited the control activity by 30%. Inhibitory effects on S-mephenytoin 4'-hydroxylation, greater than 30% of the control activity were observed ; 45% and 60% inhibitions were observed when a combination of two or three drugs was used respectively. In summary we demonstrated that cyclophosphamide, etoposide and vincristine inhibited CYP2C19-mediated metabolism competitively and that these inhibitory effects were enhanced with an increase in the number of drugs used. These results suggest that care must be exercised in the concomitant use of these three drugs and other drugs that are metabolized by CYP2C 19 in cancer chemotherapy.