Propylene glycol as a drug solvent in the study of hepatic microsomal enzyme metabolism in the rat

Propylene glycol administered ip to rats at a dose of 4 ml/kg twice a day for 3 days caused a significant elevation of the in vitro hepatic microsomal metabolism of aniline and p-nitroanisole, but at the same time caused a significant decrease in aminopyrine demethylation with no significant change in p-nitrobenzoic acid metabolism. There was no change in cytochrome P-450 concentrations with this treatment, but the response, which was dose-dependent, could not be repeated by the in vitro addition of propylene glycol to incubating systems. In vivo inhibition of drug metabolism was demonstrated by increased hexobarbital sleeping times and zoxazolamine paralysis times after propylene glycol treatment. When administered concurrently with 75 mg of phenobarbital/kg for 3 days. an additive response was obtained with aniline and p-nitroanisole metabolism. Phenobarbital appeared to abolish the depressant effects observed in aminopyrine metabolism and the slight changes observed in p-nitrobenzoic acid reduction. Kinetic studies with microsomes from treated rats showed a reduced K_m and V_max for aminopyrine demethylation, while for aniline hydroxylation there was an increase in V_max but an unchanged K_m value.