Species specificity in the metabolism of nabilone. Relationship between toxicity and metabolic routes

Abstract

1. The disposition of ¹⁴C-nabilone has been examined in dogs and monkeys; it is rapidly absorbed and extensively metabolized in both species.

2. A metabolic pathway initiated by the stereoselective enzymic reduction of the 9-keto moiety of nabilone was of major importance in the biotransformation of nabilone in the dog but was only a minor pathway in the monkey. The resulting long half-lived carbinol metabolites accounted for 77% of the circulating ¹⁴C in dog but for only 19% in monkey. 48 h after drug administration.

3. Accumulation of carbinol metabolites in brain tissue was observed in dogs, with 24 h brain concentrations being five to six times higher than the plasma concentrations. No accumulation of carbinol metabolites, nabilone or of ¹⁴C occurred in the brain of monkeys.

4. Accumulation of the carbinol metabolites in brain tissue has been implicated as the causative factor for the CNS toxicity observed in dogs treated chronically with nabilone.

5. Comparison of nabilone pharmacokinetics in dog and humans showed the dog to be unique in producing high levels of carbinol metabolites, so that monkey appeared to be a more appropriate model than dog for pre-clinical toxicological and safety studies.

6. Studies with liver 15000g supernatants indicated that the enzymic reduction of nabilone to its carbinol metabolite was a viable metabolic pathway in rat, dog and monkey, so that a distinct species difference exists between dog and monkey in the subsequent metabolism and or elimination of these carbinol metabolites.