Contribution of the metabolite 7-hydroxy-Δ1-tetrahydrocannabinol towards the pharmacological activity of Δ1tetrahydrocannabinol in mice

Tritium-labelled 7-hydroxy-Δ¹-tetrahydrocannabinol (³H-7-hydroxy-Δ¹-THC, specific activity 571 Ci/mmole) was prepared from ³H-Δ¹-THC by oxidation with a rat liver microsome preparation. Brain levels of 7-hydroxy-Δ¹-THC and Δ¹-THC in mice were measured 20 min after intravenous injection of either Δ¹-THC (2.0, 1.0 and 0.5 mg/kg) or 7-hydroxy-Δ¹-THC (1.0, 0.5 and 0.25 mg/kg) and correlated with the inhibition of spontaneous motor activity. A theoretical dose-response relationship for Δ¹-THC in the absence of the metabolite was derived on the assumption of additivity of the behavioural effects due to Δ¹THC and 7-hydroxy-Δ¹-THC present together in the mouse brain. The theoretical dose-response line for Δ¹THC and that obtained experimentally for 7-hydroxy-Δ¹-THC were parallel; on the basis of brain concentrations, 7-hydroxy-Δ¹-THC was found to be more potent than Δ¹-THC in producing behavioural changes and the calculated equipotent molar ratio was 7.1. The ratio of the concentrations of Δ¹THC and 7-hydroxy-Δ¹-THC in the mouse brain 20 min after intravenous injection of Δ¹-THC was 5.3 and the contribution of the metabolite to the overall behavioural effect was calculated as 55–63 per cent. Although metabolites of 7-hydroxyΔ¹-THC accounted for only about 10 per cent of the radioactivity present in the mouse brain 20 min after intravenous injection of ³H-7-hydroxy-Δ¹-THC, about 50 per cent of the radioactivity in the blood was present as a chromatographically more mobile material which has not yet been identified.