METABOLIC DISPOSITION OF DELTA-8-TETRAHYDROCANNABINOL AND ITS ACTIVE METABOLITES, 11-HYDROXY-DELTA-8-TETRAHYDROCANNABINOL AND 11-OXO-DELTA-8-TETRAHYDROCANNABINOL, IN MICE

Abstract

Metabolic disposition of .DELTA.8-tetrahydrocannabinol (.DELTA.8-THC), 11-hydroxy-.DELTA.8-THC (11-OH-.DELTA.8-THC), and 11-oxo-.DELTA.8-THC was studied in mouse blood, liver and brain. After administration of the cannabinoids at a dose of 10 mg/kg i.v., the concentration in blood declined biphasically. The biological half-lives of the slower phases were 32, 12 and 6 min, respectively, for .DELTA.8-THC, 11-OH-.DELTA.8-THC and 11-oxo-.DELTA.8-THC. 11-OH- and 11-oxo-.DELTA.8-THC were eliminated faster from the brain than .DELTA.8-THC. The peak levels of 11-OH- and 11-oxo-.DELTA.8-THC in the brain were higher (10.64 and 4.25 .mu.g/g, respectively) than that of .DELTA.8-THC (3.48 .mu.g/g) at 0.5 min after the i.v. injection (10 mg/kg). 11-OH- and 11-oxo-.DELTA.8-THC are distributed more readily from blood to brain in mice than is .DELTA.8-THC, and the greater pharmacological activity of the metabolites is explained, as reported previously. It was also interesting to note that a much higher level of 11-OH-.DELTA.8-THC (3.27 .mu.g/g) was found in brain than in liver (0.74 .mu.g/g) and blood (0.29 .mu.g/ml) at 15 min after the injection of 11-oxo-.DELTA.8-THC (10 mg/kg, i.v.). In this case, the levels of 11-OH-.DELTA.8-THC were always > those of 11-oxo-.DELTA.8-THC. The 11-OH-.DELTA.8-THC may be important in the pharmacological effects of 11-oxo-.DELTA.-11-oxo-.DELTA.8-THC. In additional experiments, SKF 525-A [proadifen hydrochloride] (25 mg/kg, i.p.) inhibited the metabolism of 11-OH-.DELTA.8-THC to 11-oxo-.DELTA.8-11-oxo-.DELTA.8-THC, supporting the previous suggestion that this oxidation, and the 11-hydroxylation of .DELTA.8-THC, is mediated by the microsomal monooxygenase system.