Metabolic disposition of 8α, 9α- and 8β, 9β-epoxyhexahydrocannabinols in the mouse

Metabolic disposition of 8 α, 9 α- and 8β, 9β-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 (10mg/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 8α,9α-EHHC were higher than those of 8β,9β-EHHC at all the time intervals determined. Biological half-lives in the slower phase were 17 and 13 min, respectively, for 8α,9α- and 8β,9β-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 8α,9α- and 8β,9β-EHHCs. Concentrations of 8α,9β- and 8β,9α-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 Δ⁸-tetrahydrocannabinol (Δ⁸-THC), 8α, 9α- or 8β, 9β-EHHC was injected into mice intracerebroventricularly (25 μg/head), pentobarbital (40 mg/kg, i.p.)-induced sleep prolonging effect was ranked in the following order, 8β,9β-EHHC>Δ⁸-THC>8α,9α-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 8α,9α- and 8β,9β-EHHCs to the central nervous system may cause a difference in their pharmacological effects rather than metabolic factors.