In vivo metabolism of the methyl homologues of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol and abn-delta-8-tetrahydrocannabinol in the mouse.
Methyl-delta-8-tetrahydrocannabinol (methyl-delta-8-THC), methyl-delta-9-THC and abn-methyl-delta-8-THC were synthesized by condensation of orcinol and (1S)-cis-verbenol and were administered to male Charles River CD-1 mice. Extracted hepatic metabolites were isolated by chromatography on Sephadex LH-20 and examined by gas chromatography/mass spectrometry as trimethylsilyl (TMS), (2H9)TMS and methyl ester/TMS derivatives. In addition, metabolic fractions were reduced with lithium aluminium deuteride to convert carboxylic acids to alcohols for structural correlation. Metabolites from methyl-delta-8-THC were similar with respect to the positions substituted to those produced by higher homologues; the major metabolite was methyl-delta-8-THC-11-oic acid. abn-Methyl-delta-8-THC was metabolized in a different manner. The location of the aromatic methyl group at the position adjacent to ring fusion appeared to inhibit metabolism at C(11) to a considerable extent and also to reduce the amount of the resulting alcohol from being oxidized to a carboxylic acid. This caused other metabolic pathways to become dominant, with the result that a compound containing a hydroxy group at the gem-methyl position was the major metabolite. Hydroxylation at this position has not been confirmed with any other cannabinoid, although it is thought to result in trace concentrations of hydroxy metabolites from some compounds. Metabolism of methyl-delta-9-THC was also similar to that of the higher homologues, with the exception that less metabolism occurred at C(8) and a higher percentage of the total metabolic fraction was accounted for by the 11-oic acid metabolite. Minor metabolites were mainly dihydroxy compounds and hydroxylated derivatives of delta-9-THC-11-oic acid.
Brown
N K
NK
University Department of Pharmacology, Oxford, UK.
Harvey
D J
DJ
D000535:Aluminum; D017607:Aluminum Compounds; D000818:Animals; D001711:Biotransformation; D003903:Deuterium; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008094:Lithium; D018020:Lithium Compounds; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D051379:Mice; D014297:Trimethylsilyl Compounds / Q000032:analysis
D017607:Aluminum Compounds; D018020:Lithium Compounds; D014297:Trimethylsilyl Compounds; C056263:abn-delta(8)-tetrahydrocannabinol; C055045:O-methyl-delta-9 tetrahydrocannabinol; C035731:delta-8-tetrahydrocannabinol; C056262:methyl-delta(8)-tetrahydrocannabinol; C042073:lithium aluminum hydride; D013759:Dronabinol; D008094:Lithium; D003903:Deuterium; D000535:Aluminum