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ACKNOWLEDGMENTS AND ADDRESSES
Received March 10,1976, from Centre de Recherche Merrell Inter-
Accepted for publication May 19,1976. To whom inquiries should be directed.
national, 16, rue dAnkara, F 67000 Strusbourg, France.
Pharmacokinetics of A9-Tetrahydrocannabinol in Dogs
EDWARD R. GARRETT and C. ANTHONY HUNT *
Abstract 0 The pharmacokinetics of intravenously administered 14C-Ag-tetrahydrocannabinol and derived radiolabgled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 f 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 f 3.8 ml/min, half of the hepatic plasma flow, but was 4131 f 690 ml/min referenced to un- bound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 f 0.3 min. The terminal half-life of A9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribution of 2170 f 555 liters ref- erenced to total plasma concentration was 8.2 f 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be moni- tored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 4045% of dose in feces, 14-16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue a t that time. These data were consistent with an enterohepatic recirculation of 10-15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine: 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of A9-tetrahy- drocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was in- consistent with the capability of enzyme induction to change the terminal half-life.
Keyphrases 0 As-Tetrahydrocannabinol-intravenous, radiochemical study of pharmacokinetics, dogs Pharmacokinetics-intravenous, Ag-tetrahydrocannabinol, radiochemical study, dogs Radiochemis- try-study of pharmacokinetics of intravenous A9-tetrahydrocannabinol, dogs
(-) - A9-Tetrahydrocannabinol is the major active component of marijuana. An essential prerequisite to understand its pharmacological action, presumably related
to the plasma levels of the drug and its metabolites (1,2), is the quantification of the time course of the drug and its metabolites in biological tissues to relate to the psy- choactive effects.
Agurell et al. ( 3 , 4) demonstrated that when tritium- labeled Ag-tetrahydrocannabinol was intravenously ad- ministered to the mouse and rabbit, the radioactivity was slowly excreted as metabolites in the feces and urine with no unchanged drug observed in the urine. The relative amounts excreted biliary and renally varied with the species (3-5), and enterohepatic recirculation of metabo- lites was indicated (5,6). The major studies to date with pharmacokinetic significance are those of Agurell et al. (4, 5 ) in rabbits and humans and Lemberger et al. (5 ,7 ,8) in humans. The general pattern appears to be a rapid initial fall of A9-tetrahydrocannabinol concentration in plasma with an apparent half-life of 12 min in rabbits (4) and 30 min in humans (8), with a slower decline to a terminal apparent half-life of 50-60 hr in humans (8). A similar pattern was observed in a preliminary experiment with dogs (9). Metabolite levels in human plasma increased rapidly to two to three times that of the drug (8). The slower terminal phase decline of the log metabolite level with time paralleled the similarly plotted decline of plasma A9-tetrahydrocannabinol.
It has been proposed (7,lO) that these facts can be ex- plained by concomitant rapid hepatic metabolism and distribution to binding sites and other tissues such as fat (11) with a subsequent slow release of sequestered Ag- tetrahydrocannabinol from these stores. The suggestion that induced metabolism significantly lessens the terminal half-life of A9-tetrahydrocannabinol in chronic users over that of naive individuals (2, 12) is inconsistent with this premise. The release rate from the deep tissues should be rate determining, not the metabolic rate. Changes in the latter would merely affect the relative plasma A9- tetrahydrocannabinol levels, not the terminal half-life.
The purposes of this paper are to present the results of studies designed to elucidate the rate-determining pro-
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