Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes
ABSTRACT The two most extensively studied cannabinoids, cannabidiol (CBD) and delta‐9‐tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP‐glucuronosyltransferases (UGTs). The...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Science |
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| Online Access: | https://doi.org/10.1111/cts.70119 |
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| author | Lixuan Qian Tao Zhang Jean Dinh Mary F. Paine Zhu Zhou |
| author_facet | Lixuan Qian Tao Zhang Jean Dinh Mary F. Paine Zhu Zhou |
| author_sort | Lixuan Qian |
| collection | DOAJ |
| description | ABSTRACT The two most extensively studied cannabinoids, cannabidiol (CBD) and delta‐9‐tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP‐glucuronosyltransferases (UGTs). The fractional contributions of these enzymes to cannabinoid metabolism have shown conflicting results among studies. Physiologically based pharmacokinetic (PBPK) models for CBD and THC and for drug–drug interaction studies involving CBD or THC as object drugs were developed and verified to improve estimates of these contributions. First, physicochemical and pharmacokinetic parameters for CBD, THC, and their metabolites (7‐OH‐CBD, 11‐OH‐THC, and 11‐COOH‐THC) were obtained from the literature or optimized. Second, PBPK base models were developed for CBD and THC after intravenous administration. Third, beginning with the intravenous models, absorption models were developed for CBD after oral and oromucosal spray administration and for THC after oral, inhalation, and oromucosal spray administration. The full models well‐captured the area under the concentration–time curve (AUC) and peak concentration (Cmax) of CBD and THC from the verification dataset. Predicted AUC and Cmax for CBD and 7‐OH‐CBD were within two‐fold of the observed data. For THC, 11‐OH‐THC, and 11‐COOH‐THC, 100%, 100%, and 83% of the predicted AUC values were within two‐fold, respectively, of the observed values; 100%, 92%, and 94% of the predicted Cmax values, respectively, were within two‐fold of the observed values. The verified models could be used to help address critical public health needs, including assessing potential drug interaction risks involving CBD and THC. |
| format | Article |
| id | doaj-art-477211d0eb16408d9294d2e2a3667024 |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Clinical and Translational Science |
| spelling | doaj-art-477211d0eb16408d9294d2e2a36670242025-01-24T08:17:46ZengWileyClinical and Translational Science1752-80541752-80622025-01-01181n/an/a10.1111/cts.70119Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple RoutesLixuan Qian0Tao Zhang1Jean Dinh2Mary F. Paine3Zhu Zhou4Department of Chemistry York College, City University of New York New York USADepartment of Pharmaceutical Sciences Binghamton University, the State University of New York Vestal New York USASimCYP Ltd/Certara Sheffield UKDepartment of Pharmaceutical Sciences Washington State University Pullman Washington USADepartment of Chemistry York College, City University of New York New York USAABSTRACT The two most extensively studied cannabinoids, cannabidiol (CBD) and delta‐9‐tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP‐glucuronosyltransferases (UGTs). The fractional contributions of these enzymes to cannabinoid metabolism have shown conflicting results among studies. Physiologically based pharmacokinetic (PBPK) models for CBD and THC and for drug–drug interaction studies involving CBD or THC as object drugs were developed and verified to improve estimates of these contributions. First, physicochemical and pharmacokinetic parameters for CBD, THC, and their metabolites (7‐OH‐CBD, 11‐OH‐THC, and 11‐COOH‐THC) were obtained from the literature or optimized. Second, PBPK base models were developed for CBD and THC after intravenous administration. Third, beginning with the intravenous models, absorption models were developed for CBD after oral and oromucosal spray administration and for THC after oral, inhalation, and oromucosal spray administration. The full models well‐captured the area under the concentration–time curve (AUC) and peak concentration (Cmax) of CBD and THC from the verification dataset. Predicted AUC and Cmax for CBD and 7‐OH‐CBD were within two‐fold of the observed data. For THC, 11‐OH‐THC, and 11‐COOH‐THC, 100%, 100%, and 83% of the predicted AUC values were within two‐fold, respectively, of the observed values; 100%, 92%, and 94% of the predicted Cmax values, respectively, were within two‐fold of the observed values. The verified models could be used to help address critical public health needs, including assessing potential drug interaction risks involving CBD and THC.https://doi.org/10.1111/cts.70119cannabidiolcannabinoidsdelta‐9‐tetrahydrocannabinolmetabolitesPBPKpharmacokinetics |
| spellingShingle | Lixuan Qian Tao Zhang Jean Dinh Mary F. Paine Zhu Zhou Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes Clinical and Translational Science cannabidiol cannabinoids delta‐9‐tetrahydrocannabinol metabolites PBPK pharmacokinetics |
| title | Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes |
| title_full | Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes |
| title_fullStr | Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes |
| title_full_unstemmed | Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes |
| title_short | Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta‐9‐Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes |
| title_sort | physiologically based pharmacokinetic modeling of cannabidiol delta 9 tetrahydrocannabinol and their metabolites in healthy adults after administration by multiple routes |
| topic | cannabidiol cannabinoids delta‐9‐tetrahydrocannabinol metabolites PBPK pharmacokinetics |
| url | https://doi.org/10.1111/cts.70119 |
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