Studies on the beta-oxidative metabolism of delta 1- and delta 6-tetrahydrocannabinol in the mouse. The in vivo biotransformation of metabolites oxidized in the side chain

Abstract

The metabolism of 5"-hydroxy-delta 1-tetrahydrocannabinol (THC), 5"-hydroxy-[5",5"-2H2]delta 1-THC, delta 1-THC-5"-oic acid, and delta 6-THC-5"-oic acid was examined by combined gas chromatography and mass spectrometry in the mouse after intraperitoneal administration of the compounds. Metabolic profiles from all three derivatives of delta 1-THC were similar and showed extensive metabolism by the beta-oxidation pathway. Nine metabolites were identified, seven of which contained a C3 side chain. The major metabolite from the delta 1-THC derivatives was 7-hydroxy-4",5"-bis,nor-delta 1-THC-3"-oic acid. Similar metabolites were found with delta 6-THC-5"-oic acid. No metabolites were found with even numbers of carbon atoms in the side chain although these have been reported to be produced in vivo by THC and several other cannabinoids in several species. Thus, the beta-oxidation route, after initial hydroxylation at C-5", appears to be directly responsible for formation of side chain-degraded cannabinoid metabolites containing odd numbers of carbon atoms in the chain but not initially for those metabolites containing an even number of carbon atoms. These are presumed to be formed by initial alpha-oxidation to give a C4 side chain which can then undergo beta-oxidation to the cannabinoids with C2 side chains. The extensive beta-oxidation observed in these experiments, coupled with the absence of corresponding cannabinoids from delta 1-THC itself in the mouse, suggests that 5"-hydroxylation is the rate-determining step in the formation of these compounds.