Unlike drugs such as alcohol which are cleared rapidly from the body, cannabinoids are very lipophilic and will distribute to the fatty tissue, a process which leads to considerable accumulation. This in turn appears to produce a chronic state of partial anaesthesia probably as the result of partition of the psychoactive cannabinoids, delta-9-tetrahydrocannabinol (delta-9-THC) and its 11-hydroxy metabolite into membranes. Being lipophilic, the drug is also a good substrate for membrane-bound enzymes such as cytochrome P-450 which produce a number of psychoactive metabolites. The long-term aims of the project are, therefore, to evaluate the role of tissue distribution and metabolism in the production of adverse effects by cannabis, particularly those relating to drug accumulation; this is a major hazard of this drug in man. The project can be divided into four topics: 1. Examination of the role of cytochrome P-450 isozymes in the production of metabolites of delta-9-THC with particular reference to their role in producing toxic metabolites and in defining differences between metabolic profiles from various tissues and species. Isozymes of P-450 will be isolated by chromatofocussing and immuno-affinity chromatography and fractions reconstituted for metabolic studies by combined gas chromatography/mass spectrometry (GC/MS). Knowledge gained from these studies will also be applied to the study of toxic metabolites from other lipophilic drugs of abuse. 2. Examination of the influence of factors such as changes in lipophilicity on metabolic profiles - studies to be conducted with THC homologues in vivo and in vitro using mice and guinea-pigs as animal models. 3. Examination of conjugates formed by interaction of delta-9-THC with lipid metabolism, particularly with fatty acids and phospholipids together with the effect of these conjugates on membrane fluidity as measured by electron spin resonance. Possible compensatory changes in membrane structure, particularly fatty acid unsaturation, will also be examined. 4. Improvements to our existing technique based on GC/MS with metastable ion monitoring for quantification of delta-9-THC and its major metabolites with the aim of developing, for the first time, a method sensitive enough to define fully the pharmacokinetics and accumulation of the drug in humans.
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