Metabolic disposition of 8 alpha, 9 alpha- and 8 beta, 9 beta-epoxyhexahydrocannabinols in the mouse

Metabolic disposition of 8 alpha, 9 alpha- and 8 beta, 9 beta-epoxyhexahydrocannabinols (EHHCs) was studied using mice to clarify mechanisms which cause a difference in their pharmacological activities. At given time intervals from 0.5 to 60 min after intravenous injections of 8, 9-EHHCs (10 mg/kg), levels of unchanged epoxides extracted from blood, liver and brain of mice were determined by gas chromatography. Blood levels of both epoxides declined biphasically, and the concentrations of 8 alpha, 9 alpha-EHHC were higher than those of 8 beta, 9 beta-EHHC at all the time intervals determined. Biological half-lives in the slower phase were 17 and 13 min, respectively, for 8 alpha, 9 alpha-and 8 beta 9 beta-EHHCs. A similar result was obtained for 8,9-EHHCs concentrations in the liver. However, no significant difference in the brain levels was found between 8 alpha, 9 alpha-and 8 beta, 9 beta-EHHCs. Concentrations of 8 alpha, 9 beta-and 8 beta, 9 alpha-dihydroxyhexahydrocannabinols as well as unchanged epoxides 15 min after 8, 9-EHHCs injections increased significantly in the liver of mice pretreated with SKF 525-A (25 mg/kg, i.p.) comparing with the control. When delta 8-tetrahydrocannabinol (delta 8-THC), 8 alpha, 9 alpha- or 8 beta, 9 beta-EHHC was injected into mice intracerebroventricularly (25 micrograms/head), pentobarbital (40 mg/kg, i.p.)-induced sleep prolonging effect was ranked in the following order, 8 beta, 9 beta-EHHC greater than delta 8-THC greater than 8 alpha, 9 alpha-EHHC. These results suggest that monooxygenase system involving cytochrome P-450 and epoxide hydrolase together play important roles in the epoxides metabolism. In addition, different activities of 8 alpha, 9 alpha-and 8 beta, 9 beta-EHHCs to the central nervous system may cause a difference in their pharmacological effects rather than metabolic factors.