Document Detail


Tolerance and disposition of tetrahydrocannabinol in man.
MedLine Citation:
PMID:  6256518     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The hypothesis was tested that the development of tolerance in man to the pharmacological effects of delta 9-tetrahydrocannabinol (THC) is due in part to changes in metabolism and disposition. Tolerance developed in six subjects following p.o. administration of 30 mg of THC every 4 hr for 10 to 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: 1) average total metabolic clearance and the initial apparent volume of distribution increased from 605 to 977 ml/min and from 2.6 to 6.4 liters, respectively; 2) steady-state volume of distribution, averaging 684 liters, was unaltered; 3) the majority of model-dependent pharmacokinetic parameters as well as the time course of total metabolites in plasma were unchanged; 4) the percent dose excreted in urine decreased from 23.2 to 17.5%, but total elimination (urine plus feces) was not significantly changed; and 5) metabolites were rapidly formed (t 1/2 = 2.8-4.4 min), but slowly eliminated (t 1/2 = 49-53 hours) because of extensive protein binding. Renal clearance values of total metabolites were surprisingly low (maximum of 18-20 ml/min) and decreased with time (approximately 1 ml/min after 4-5 days), indicating the accumulation of highly bound metabolites. We conclude that such pharmacokinetic and metabolic changes cannot account for the development of tolerance to the cardiovascular, psychological and skin hypothermic effects of THC.
Authors:
C A Hunt; R T Jones
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  215     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1980 Oct 
Date Detail:
Created Date:  1981-03-27     Completed Date:  1981-03-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  35-44     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Body Temperature / drug effects
Drug Tolerance*
Euphoria / drug effects
Heart Rate / drug effects
Humans
Male
Models, Biological
Tetrahydrocannabinol / metabolism*
Grant Support
ID/Acronym/Agency:
DA-01696/DA/NIDA NIH HHS; DA-01773/DA/NIDA NIH HHS; HSM-42-73181/HS/AHRQ HHS
Chemical
Reg. No./Substance:
1972-08-3/Tetrahydrocannabinol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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