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It was already reported that a masked compound, cyclophosphamide (Endoxan, EX) undergoes the first step metabolism by a drug-metabolizing enzyme in liver microsomes, cytochrome P-450. By pretreatment with phenobarbital as an inducer of P-450, the maximum blood level of active metabolites of EX (normustard-like substances) in normal rats was 2.3 times higher than that in non-treated rats, in conformity with the increase in amount of liver P-450 and in alkylating activity of EX. In YS (Yoshida sarcoma)-bearing rats, the value of liver P-450 went down day by day to 1/2 on the 4th day after inoculation, but it remained normal when animals were pretreated with phenobarbital. In parallel with this, the blood level of normustard-like substances after EX administration was normal or showed a tendency toward increase. In 11 clinical cases pretreated with phenobarbital, the blood level of normustard-like substances 1 to 3 hr after EX administration, at the time when it reaches the peak was 1.5 times higher on an average than that in cases without pretreatment.

Effects of inducer of liver drug-metabolizing enzyme on blood level of active metabolites of cyclophosphamide in rats and in cancer patients.