TOLERANCE AND DISPOSITION OF TETRAHYDROCANNABINOL IN MAN

  • 1 January 1980
    • journal article
    • research article
    • Vol. 215  (1) , 35-44
Abstract
The development of tolerance in man to the pharmacological effects of .DELTA.9-tetrahydrocannabinol (THC) may be due in part to changes in metabolism and disposition. Tolerance developed in 6 subjects following p.o. [per os] administration of 30 mg THC every 4 h for 10-12 days. Evaluation of THC pharmacokinetics was based on plasma levels of unchanged THC following i.v. administration of [14C] THC before and after the chronic p.o. THC. Development of tolerance was paralleled by pharmacokinetic changes: average total metabolic clearance and the initial apparent volume of distribution increased from 605-977 ml/min and from 2.6 to 6.4 l, respectively. Steady-state volume of distribution, averaging 684 l, was unaltered. The majority of model-dependent pharmacokinetic parameters and the time course of total metabolites in plasma were unchanged. The percent dose excreted in urine decreased from 23.2 to 17.5%, but total elimination (urine plus feces) was not significantly changed. Metabolites were rapidly formed (t1/2 [half-life] = 2.8-4.4 min), but slowly eliminated (t1/2 = 49-53 h) due to extensive protein binding. Renal clearance values of total metabolites were surprisingly low (maximum of 18-20 ml/min) and decreased with time (.apprx. 1 ml/min after 4-5 days), indicating the accumulation of highly bound metabolites. Such pharmacokinetic and metabolic changes cannot account for the development of tolerance to the cardiovascular, psychological and skin hypothermic effects of THC.