Metabolism of delta1-tetrahydrocannabinol by rats tolerant to cannabis.

Abstract

Daily treatment of rats with phenobarbital, 75 mg/kg, for 5 days resulted in an induction of the metabolism of 14C-Δ1-transterahydrocannabinol (THC) in vitro and in vivo. Although the Km and Vmax for THC metabolism by liver preparations in vitro were not altered, the rate of formation of highly polar THC metabolites was significantly increased and the final concentration of 7-hydroxy-Δ1-THC was decreased. Phenobarbital also significantly increased the rate of biliary excretion of THC and its metabolites and their disappearance from the blood and tissues.In one experiment, rats receiving a marihuana extract daily (providing THC, 5–10 mg/kg) failed to gain body weight during the first week of treatment, but then became tolerant to this effect. But neither the rate of THC metabolism in vitro nor the pattern of metabolites formed was influenced in the tolerant animals compared to controls. In another experiment, rats were shown to become tolerant on chronic treatment with marihuana extract, as indicated by a reduction in marihuana-induced enhancement of ethanol sleeping time. The biliary excretion, disappearance from the blood, and residual tissue levels of THC and its metabolites were not altered in the tolerant animals compared to pair-fed and ad libitum-fed controls. Therefore the mechanism of tolerance development to cannabis in the rat is more likely of CNS than of metabolic origin.