THE IN VITRO AND IN VIVO METABOLISM OF ^6a,10a DIMETHYL HEPTYL TETRAHYDROCANNABINOL (DMHP)

¹ Lilly Laboratory for Clinical Research, Marion County General Hospital and The Lilly Research Laboratories, Indianapolis, Indiana

¹⁴C-^{6a, 10a} dimethyl heptyl tetrahydrocannabinol (DMHP) is metabolized to three more polar metabolites by the 9000 x g liver supernatant of several animal species. Under our in vitro conditions, rabbits and mice metabolize DMHP to a greater extent than rats, guinea pigs and dogs, the latter possessing the least activity. DMHP metabolism by rabbit liver is markedly diminished by incubation in nitrogen and in the presence of boiled enzyme. After the intravenous administration of DMHP to rats and rabbits, the rate of disappearance of the parent compound and its metabolites from plasma is biphasic. The T of the secondary slow phase is about 24 hours in both species. One to three hours after DMHP administration the highest concentration of radioactivity is present in liver, lung and spleen. The concentration in the brain is low compared to other tissues. In the rat 70% of the administered dose of radioactivity was recovered after ¹⁴C-DMHP administration (4% in urine and 66% in feces). In the rabbit 87% of ¹⁴C was recovered (24% in urine and 63% in feces). The metabolites in feces appeared to be neutral compounds, whereas the major portion of the urinary metabolites was acidic in nature. In rabbits the plasma half-life and pattern of excretion of DMHP are different from that reported to occur with ⁹-tetrahydrocannabinol. The results suggest that in the rabbit the prolonged plasma T seen after DMHP administration may be related in part to a different excretory pathway for DMHP as opposed to that found after ⁹-tetrahydrocannabinol administration to this species.