STUDIES ON THE MECHANISM OF MEPROBAMATE TOLERANCE IN THE RAT

¹ Department of Pharmacology, Purdue University, West Lafayette, Indiana

The development of tolerance to meprobamate in rats was investigated by the measurement of whole body activity before and after the administration of meprobamate to meprobamate-pre-treated and control animals. The results indicate that tolerance to meprobamate does develop in rats following the daily administration of meprobamate for 35 days.

Further studies revealed that after reaching essentially the same levels initially in both tolerant and nontolerant rats, the brain and blood C¹⁴ levels, representative of unchanged meprobamate, as well as fat and muscle C¹⁴ levels, decreased at a more rapid rate in tolerant than in nontolerant animals. It was also observed that urinary excretion in tolerant rats was more rapid at early time intervals than in nontolerant animals, although the total amount excreted by both groups in 24 hours was essentially the same. Metabolite studies demonstrated that nontolerant animals excreted nearly twice as much unchanged meprobamate as tolerant rats. These findings demonstrate that increased metabolic inactivation plays an important role in the development of meprobamate tolerance.