Pharmacokinetic/Pharmacodynamic Modeling of the Acute Heart Rate Effects of Delta-9 Tetrahydrocannabinol and Its Major Metabolites After Intravenous Injection in Healthy Volunteers.
W R Wolowich, R Greif, L Theiler, Maren Kleine-Brueggeney
{"title":"Pharmacokinetic/Pharmacodynamic Modeling of the Acute Heart Rate Effects of Delta-9 Tetrahydrocannabinol and Its Major Metabolites After Intravenous Injection in Healthy Volunteers.","authors":"W R Wolowich, R Greif, L Theiler, Maren Kleine-Brueggeney","doi":"10.1007/s13318-025-00941-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.</p><p><strong>Methods: </strong>The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.</p><p><strong>Results: </strong>The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.</p><p><strong>Conclusion: </strong>THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.</p><p><strong>Trial registration: </strong>www.isrctn.com ; registration number ISRCTN53019164.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-025-00941-8","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and objectives: Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.
Methods: The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.
Results: The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.
Conclusion: THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.
Trial registration: www.isrctn.com ; registration number ISRCTN53019164.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
