Differential stimulation of diphenhydramine, pethidine, morphine and aniline metabolism by chronic methaqualone treatment.

In the present study, the effect of chronic oral methaqualone treatment (60 mg/kg/24 h for 25 days) was examined on the metabolism of diphenhydramine, pethidine, morphine and aniline in rat liver microsomes. Such chronic methaqualone treatment caused an enhancement of microsomal drug metabolizing enzymes catalyzed N-demethylations of diphenhydramine, pethidine, morphine and aromatic hydroxylation of aniline. A single oral dose of methaqualone (60 mg/kg) did not result in any significant change in the activities of drug metabolizing enzymes. Methaqualone inhibited drug metabolizing enzymes when used at final concentrations of 1 and 3 mmol/l in vitro. These observations led to suggest that the stimulation of drug metabolism noted in this study is possibly due to the induction of microsomal drug metabolizing enzymes. It was interesting to note that the induction of N-demethylases by repeated methaqualone intake was differential in nature since diphenhydramine and morphine N-demethylases were induced about twofold whereas pethidine N-demethylase was enhanced about fourfold. These results should be of extreme importance in understanding the biochemical mechanism of the specific and differential drug tolerance by continued methaqualone abuse and its possible interaction with other drugs.