Clinical Pharmacokinetics of Cannabinoids

ABSTRACT Absorption and metabolism of tetrahydrocannabinol (THC) vary as a function of route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, while psychotropic effects start within seconds to a few minutes, reach a maximum after 15 to 30 minutes, and taper off within 2 to 3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30 to 90 minutes, reach their maximum after 2 to 3 hours, and last for about 4 to 12 hours, depending on dose and specific effect. The initial volume of distribution of THC is small for a lipophilic drug, equivalent to the plasma volume of about 2.5–3 L, reflecting high protein binding of 95–99%. The steady state volume of distribution has been estimated to be about 100 times larger, in the range of about 3.5 L per kg of body weight. The lipophility of THC with high binding to tissue and in particular to fat, the major long-term storage site, causes a change of distribution pattern over time. Only about 1% of THC administered IV is found in the brain at the time of peak psychoactivity. THC crosses the placenta and small amounts penetrate into the breast milk. Metabolism of THC occurs mainly in the liver by microsomal hydroxylation and oxidation catalyzed by enzymes of the cytochrome P-450 complex. In man, the C-11 carbon is the major site attacked. Hydroxylation results in 11-hydroxy-THC (11-OH-THC) and further oxidation to 11-nor-9-carboxy-THC (THC-COOH), which may be glucuronated to THC-COOH beta-glucuronide. Pharmacologically, 11-OH-THC shows a similar profile as THC while THC-COOH is devoid of psycho-tropic effects. With oral administration higher amounts of 11-OH-THC are formed than with inhalation, reaching similar plasma levels as its parent drug, and contributing significantly to the overall effects of THC. Metabolic interaction between THC and the non-psychotropic cannabidiol (CBD) is based on inhibition of the cytochrome P-450-3A enzyme by CBD. Repeated administration of all cannabinoids causes induction of some cytochrome P-450 isoenzymes which may result in interactions with other medical and non-medical drugs that are using the same enzymes for metabolism.