Abstract

(+)-trans-delta 8-Tetrahydrocannabinol (THC) was synthesized by condensation of (1R)-cis-verbenol and olivetol, and its in vitro and in vivo hepatic metabolism was studied in male mice. Metabolites were isolated by solvent extraction, purified, in the case of the in vivo study, by chromatography on Sephadex LH-20, and identified by combined gas chromatography/mass spectrometry. Twenty-three metabolites were identified. These were similar to those from the (-)-isomer in that the major metabolic route was hydroxylation at C-11 followed, in vivo, by oxidation to the corresponding acid. Further hydroxylation of these compounds at C-7 and in the side chain led to a series of disubstituted metabolites. The major sites of side chain hydroxylation were 1'-, 3'-, and 4'-. Less 2'-hydroxylation was observed than with the (-)-isomer, but the major difference between the two isomers was the production of 1'-hydroxy metabolites only from the (+)-isomer. Much less hydroxylation occurred at C-7 than with the (-)-isomer so that the 7,11-disubstituted compounds, which were major metabolites of (-)-trans-delta 8-THC, were formed in insignificant concentrations. Another difference between the metabolism of the two isomers, in vitro, was the presence of substantial concentrations of monohydroxy metabolites containing hydroxylation in the side chain; these compounds are absent in metabolic profiles from (-)-trans-delta 8-THC. An epoxide and its derived glycol were detected in vitro. Another major in vitro metabolic route was the formation of an acetate derivative of 11-hydroxy-(+)-trans-delta 8-THC.(ABSTRACT TRUNCATED AT 250 WORDS)