In vitro metabolism of delta-11-tetrahydrocannabinol in the mouse, rat, guinea pig, rabbit, hamster, gerbil and cat.
1. Liver microsomes were prepared from rats, rabbits, guinea pigs, hamsters, gerbils, a cat and three strains of mice, and were incubated with delta-11-tetrahydrocannabinol (delta-11-THC). The extracted metabolites were separated by chromatography on Sephadex LH-20 and examined by gas chromatography and combined gas chromatography/mass spectrometry. 2. Eleven metabolites were identified; these were formed by aliphatic hydroxylation of all positions of the pentyl chain, allylic hydroxylation at C-10 and C-8 (alpha and beta), and by the epoxide-diol pathway. 3. The ratio of the metabolites varied considerably between the species. Mice and rats favoured hydroxylation at C-8-alpha with very little hydroxylation of the pentyl chain. 4. In the guinea pig, however, hydroxylation of the pentyl chain, particularly at C-4', produced the major metabolites; very little hydroxylation occurred at C-8. 5. Side-chain hydroxylation was also favoured by the gerbil. 6. In the cat and hamster, 8-beta-hydroxylation was by far the major metabolic route, accounting, in the cat, for nearly 70% of the recovered metabolites. 7. The rabbit, on the other hand, favoured the epoxide-diol pathway with over 70% of the recovered metabolites being accounted for by the 9,11-dihydro-diols. 8. The results emphasise the need to make appropriate choices of animal models for metabolic and toxicological studies in humans.
Harvey
D J
DJ
University Department of Pharmacology, Oxford, UK.
Brown
N K
NK
D000818:Animals; D002415:Cats; D006224:Cricetinae; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005849:Gerbillinae; D006168:Guinea Pigs; D006900:Hydroxylation; D013058:Mass Spectrometry; D008647:Mesocricetus; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
C052413:delta(9-11)-tetrahydrocannabinol; D013759:Dronabinol