Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women

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Abstract
A comparative study was done in women and men of the effects of .DELTA.9-tetrahydrocannabinol [the psychoactive constituent found in Cannabis sativa] (.DELTA.9-THC), i.v. or orally, on dynamic activity, metabolism, excretion and kinetics. In general, no differences between the 2 sexes were observed. .DELTA.9-THC is converted by microsomal hydroxylation to 11-hydroxy-.DELTA.9-THC (11-OH-.DELTA.9-THC), which is both a key intermediate for further metabolism to 11-nor-.DELTA.9-TCH-9-carboxylic acid (11-nor-acid) by liver alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11-OH-.DELTA.9-THC to that of .DELTA.9-THC in plasma were found after i.v. dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11-nor-acids and the related, more polar acids. Urinary excretion of .DELTA.9-THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 h, mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13-17% of the total dose. After 72 h, the cumulative fecal excretion for both sexes after i.v. administration ranged from 25-30%; after oral administration the range was 48-53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11-OH-.DELTA.9-THC were particularly noteworthy. Kinetics of .DELTA.9-THC and metabolites were much the same for the female and male subjects. For .DELTA.9-THC, terminal-phase t1/2 [half-life] for both sexes, irrespective of the route, ranged from 25-36 h. A comparison of the results for AUC[area under the concentration-time curve]/dose (.DELTA.9-THC) after oral dosing with comparable data from i.v. administration indicated bioavailability of the order of 10-20% for both sexes. After i.v. .DELTA.9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).