Pharmacokinetics.

Marinol® capsules contain synthetic THC dissolved in sesame seed oil. Oral THC demonstrates low (6% to 20%) and variable bioavailability among test subjects. Gastric acidity causes some isomerization of THC to the delta-8-derivative and the drug is subject to a significant first pass effect. Peak plasma concentrations of THC are achieved within 1 to 6 hours, but may remain elevated for several hours. Initially, THC is oxidized in the liver to 11-hydroxy-THC, a potent psychoactive metabolite. Other minor hydroxylated metabolites also are formed. Major urinary metabolites are formed by further oxidation of 11-OH-THC and other hydroxylated metabolites to carboxylic acid derivatives and other polar acids, which are eliminated in the urine and feces as conjugated and unconjugated metabolites.

Although THC is cleared rapidly by the liver (hepatic clearance = 950 mL/min), it has a very large volume of distribution (» 10 L/kg).24 Thus, the terminal half-life of THC is on the order of 20 to 36 hours. With chronic use, the limiting step for elimination is redistribution from peripheral tissues.

Following inhalation, THC is rapidly absorbed into the blood stream and redistributed. Considerable amounts of the dose contained in one cigarette are lost in side stream smoke and destroyed by pyrolysis. Peak blood levels of THC are achieved at the end of smoking and then decline rapidly over the next 30 minutes. Smoked marijuana is associated with much larger peak plasma THC concentrations, but a shorter duration of effect than orally administered THC. The time course of plasma concentrations after smoking marijuana is similar to that obtained after intravenous administration. Considerably smaller amounts of 11-OH-THC are formed when THC is inhaled, as compared with the oral route.