{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:37:35Z","timestamp":1791859055893,"version":"4.3.4"},"reference-count":66,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse (NIDA)","award":["F31-DA056197"],"award-info":[{"award-number":["F31-DA056197"]}]},{"name":"National Institute on Drug Abuse (NIDA)","award":["#2018F-ADARP"],"award-info":[{"award-number":["#2018F-ADARP"]}]},{"name":"National Institute on Drug Abuse (NIDA)","award":["171"],"award-info":[{"award-number":["171"]}]},{"name":"Washington State University","award":["F31-DA056197"],"award-info":[{"award-number":["F31-DA056197"]}]},{"name":"Washington State University","award":["#2018F-ADARP"],"award-info":[{"award-number":["#2018F-ADARP"]}]},{"name":"Washington State University","award":["171"],"award-info":[{"award-number":["171"]}]},{"name":"State of Washington Initiative Measure","award":["F31-DA056197"],"award-info":[{"award-number":["F31-DA056197"]}]},{"name":"State of Washington Initiative Measure","award":["#2018F-ADARP"],"award-info":[{"award-number":["#2018F-ADARP"]}]},{"name":"State of Washington Initiative Measure","award":["171"],"award-info":[{"award-number":["171"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug\u2013drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration\u2019s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5\u201310% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs.<\/jats:p>","DOI":"10.3390\/pharmaceutics16121599","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T06:48:39Z","timestamp":1734331719000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of the Drug\u2013Drug Interaction Potential of Cannabidiol Against UGT2B7-Mediated Morphine Metabolism Using Physiologically Based Pharmacokinetic Modeling"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-9298","authenticated-orcid":false,"given":"Shelby","family":"Coates","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E Spokane Falls Blvd., Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keti","family":"Bardhi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E Spokane Falls Blvd., Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhagwat","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E Spokane Falls Blvd., Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Lazarus","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E Spokane Falls Blvd., Spokane, WA 99202, USA"},{"name":"Division of Quantitative Molecular Biosciences, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, 160 Hayes Rd., Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0885-3924(01)00396-7","article-title":"Chronic pain prevalence and analgesic prescribing in a general medical population","volume":"23","author":"Clark","year":"2002","journal-title":"J. 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