A study of the liver N-demethylase activity in rats treated with different dosage schedule of morphine, or with a single dose of haloperidol was carried out. It was found that prolonged administration of morphine to rats inhibited the rate of ethylmorphine demethylation in vitro and diminished the liver cytochrome P450 level. Therefore, it could be assumed that the changes in N-demethylase activity did not play a substantial role in altering of morphine pharmacokinetics. Haloperidol, when given to rats, did not change the microsomal N-demethylase activity in vitro; however, when introduced into incubation mixture, it inhibited the rate of ethylmorphine dealkylation. This indicated that elevation of morphine level in rats by haloperidol was more likely due to a competitive mechanism.
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