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 Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. Δ 9 ‐THC is converted by microsomal hydroxylation to 11‐hydroxy‐Δ 9 ‐THC (11‐OH‐Δ 9 ‐THC), which is both a key intermediate for further metabolism to 11‐nor‐Δ 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‐Δ 9 ‐THC to that of Δ 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 Δ 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‐Δ 9 ‐THC were particularly noteworthy. Kinetics of Δ 9 ‐THC and metabolites were much the same for female and male subjects. For Δ 9 ‐THC, terminal‐phase t½s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AU C i dose (Δ 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 Δ 9 ‐THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes). Clinical Pharmacology and Therapeutics (1983) 34 , 352–363; doi: 10.1038/clpt.1983.179