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

A comparative study was done in women and men of the effects of delta 9-tetrahydrocannabinol (delta 9-THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two 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-THC-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 intravenous 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 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 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 female and male subjects. For delta 9-THC, terminal-phase t1/2s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AUC/dose (delta 9-THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous delta 9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).