Metabolism of Δ 1-tetrahydrocannabinol by the rat in vivo and in vitro

Abstract

The metabolism of [ 14C]Δ 1-tetrahydrocannabinol (THC) was examined in vitro employing the 10.000 g supernatant (10 KS) of rat liver homogenates, after determination of apparent optimal conditions. The extent of metabolism was greater when THC was added as a suspension in rat serum than in a glycol or ethanol solution. The apparent K m for THC metabolism by the 10 KS was found to be 1.35 × 10 −4M and the apparent v max was 0.18 μg THC metabolized/mg of protein/min. Thin-layer chroma tography indicated that at least seven metabolites were produced from THC, with the quantitative pattern of the metabolites changing dramatically with increasing duration of incubation. The major metabolite of 7-hydroxy-Δ 1-THC appeared to be 6,7-dihydroxy-Δ 1-THC. The dihydroxylated compound was slowly metabolized to more polar compounds. The bile was verified to be a major route of THC elimination in the rat. accounting for 60 per cent of an i.v. dose of THC (3 mg/kg) within 3 hr. Biliary excretion reached a maximum rate at THC doses of 6 and 12 mg/kg. Only traces of unchanged THC were found in the bile, and less than 5 per cent of a dose was excreted as 7-hydroxy-THC, the metabolites in the bile all being highly polar. The metabolism of THC, rather than the excretory process, was apparently the rate-limiting step in the elimination of the drug in the bile. When the biliary excretary mechanism was saturated, increase in the dose of THC resulted in increased urinary excretion of highly polar metabolites, but relative concentrations in tissues other than liver were unaffected.