title: Oxidative cleavage of the pentyl side-chain of cannabinoids. Identification of new biotransformation pathways in the metabolism of 4'-hydroxy-delta-9-tetrahydrocannabinol in the mouse.
abstract: During an investigation of the mechanisms leading to the formation of metabolites of cannabinoids in which the pentyl side chain is reduced to 2, 3 or 4 carbon atoms, the further metabolism of 4'-hydroxy-delta 9-tetrahydrocannabinol was investigated in vivo in mice. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and identified by GC/MS. Ten metabolites were identified and a further two had tentative structural assignments made. The major metabolic route, in common with that seen with most cannabinoids, was hydroxylation at the allylic 11-position, followed by oxidation to a carboxylic acid. Additional hydroxylation occurred at C-8. Abundant metabolites were also formed by oxidative cleavage of the pentyl side chain. The major metabolites of this type had lost the terminal two carbon atoms to give compounds containing a carboxyethyl side chain. This is the major product normally produced by beta-oxidation of the acid formed from 5'-hydroxy-delta 9-tetrahydrocannabinol. Trace concentrations of two other acids that appeared to have a carboxypropyl side chain were also found. The results show that, in addition to beta-oxidation, initiated by hydroxylation at the 5'-carbon atom (omega-hydroxylation), at least one other oxidative route, initiated by omega-1-hydroxylation, is involved in the production of metabolites with two carbon atoms missing from the pentyl side chain. This pathway does not seem to have been characterized as a biotransformation mechanism in drug metabolism and a possible mechanism is suggested.
authors.affiliation: University Department of Pharmacology, Oxford, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Harvey
mesh_terms: D000535:Aluminum; D017607:Aluminum Compounds; D000818:Animals; D001711:Biotransformation; D002186:Cannabinoids / Q000378:metabolism* / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002621:Chemistry; D003903:Deuterium; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D008094:Lithium; D018020:Lithium Compounds; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D014297:Trimethylsilyl Compounds / Q000378:metabolism
chemical_list: D017607:Aluminum Compounds; D002186:Cannabinoids; D018020:Lithium Compounds; D014297:Trimethylsilyl Compounds; C065132:4'-hydroxy-delta(9)-tetrahydrocannabinol; C042073:lithium aluminum hydride; D013759:Dronabinol; D008094:Lithium; D003903:Deuterium; D000535:Aluminum