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THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP\u2010glucuronosyltransferases (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\u2013drug 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\u2010OH\u2010CBD, 11\u2010OH\u2010THC, and 11\u2010COOH\u2010THC) 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\u2010captured the area under the concentration\u2013time curve (AUC) and peak concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) of CBD and THC from the verification dataset. Predicted AUC and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> for CBD and 7\u2010OH\u2010CBD were within two\u2010fold of the observed data. For THC, 11\u2010OH\u2010THC, and 11\u2010COOH\u2010THC, 100%, 100%, and 83% of the predicted AUC values were within two\u2010fold, respectively, of the observed values; 100%, 92%, and 94% of the predicted <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> values, respectively, were within two\u2010fold 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.<\/jats:p>","DOI":"10.1111\/cts.70119","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T05:54:19Z","timestamp":1735883659000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta\u20109\u2010Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3137-5529","authenticated-orcid":false,"given":"Lixuan","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Chemistry York College, City University of New York  New York 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