Interactions of several cannabinoids with the hepatic drug metabolizing system

Spectral interactions of various cannabinoids with rat liver musomes and their effects on several musomal enzymes were studied. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), cannabinol (CBN), and cannabidiol (CBD) produced type I spectral changes; the spectral dissociation constants K_s were 42, 37, 46 and 11·2 μM, respectively,. Aminopyrine demethylation was competitively inhibited by Δ⁸-THC, Δ⁸-THC, CBN and CBD, by the latter only in concentrations below 10 μM. The inhibitor constants were found to be 58, 60, 68 and 49 μM, respectively. In a similar way morphine demethylation was inhibited. Δ⁸-THC, however, did not inhibit this reaction, and inhibition by CBD was of mixed type at all concentrations. There was no effect of cannabinoids on aniline hydroxylation. The inhibitory potencies of cannabis constituents on drug metabolism in vitro parallel the in vivo results obtained by interaction studies with hexobarbitone. It must be concluded that CBD, which is by far more potent in inhibiting drug metabolism than other cannabinoids, contributes significantly to the effects of crude cannabis preparations at least in rodents.