Pharmacokinetics of delta 9-tetrahydrocannabinol in rabbits following single or multiple intravenous doses.

The pharmacokinetics of delta 9-tetrahydrocannabinol (delta 9-THC) has been studied in rabbits under conditions of single or multiple administration. Measurement of the drug was by a sensitive GC/MS technique using metastable ion monitoring and capable of measuring 0.005 ng/ml of the drug in plasma. This method enabled measurements of the drug to be made for 8-10 days after a single iv dose of 1 mg/kg of delta 9-THC and for 26 days following treatment for 22 days with the same dose. Plasma concentration-time data were analyzed by least squares nonlinear regression with the program NONLIN and terminal half-lives in the range 30-66 hr [mean 47.1 +/- 3.5 (SE), n = 8] were found after acute drug treatment. These increased to 74.6 +/- 1.7 hr (n = 4) after an 8-day treatment and to 83.0 hr after the 22-day treatment. Plasma clearance values were high, but the large amount of drug sequestered in tissues, reflected by large volumes of distribution, was the main determinant of terminal half-life. Measurements of the drug in several tissues indicated that fat was the major site of sequestration. The relative concentrations of delta 9-THC in the various tissues were similar to those observed for other lipophilic compounds, suggesting that distribution of delta 9-THC is governed by its physicochemical properties and not by any active transport process or specific barriers.