Coates Shelby, Bardhi Keti, Prasad Bhagwat, Lazarus Philip
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, 412 E Spokane Falls Blvd., Spokane, WA 99202, USA.
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.
Pharmaceutics. 2024 Dec 16;16(12):1599. doi: 10.3390/pharmaceutics16121599.
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-drug interactions (DDIs). 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. 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. While these predicted increases in morphine exposure are below the Food and Drug Administration's cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5-10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs.
吗啡是一种常用的阿片类镇痛药，用于治疗慢性疼痛。吗啡通过尿苷二磷酸葡萄糖醛酸基转移酶（UGT）2B7进行葡萄糖醛酸化，形成吗啡-3-葡萄糖醛酸苷和吗啡-6-葡萄糖醛酸苷。吗啡是慢性疼痛管理的金标准，治疗指数较窄。报告显示，慢性疼痛患者越来越多地使用其他补充剂来治疗慢性疼痛，包括大麻二酚（CBD）。高达50%的慢性疼痛患者报告称，他们将大麻与处方阿片类药物（包括吗啡）联合使用以控制疼痛。先前的研究表明，大麻二酚是UGT2B7的强效抑制剂，包括对吗啡介导的代谢的抑制。吗啡和CBD联合使用可能会导致不良的药物相互作用（DDIs）。利用现有的理化和临床参数，在健康人群和肝硬化人群中开发并验证了吗啡和CBD的基于生理的药代动力学（PBPK）模型。然后将这两个人群的模型结合起来，预测在健康和肝损伤虚拟人群中同时服用吗啡和CBD期间潜在DDIs的严重程度和临床相关性。预测性DDI模型表明，健康人群中吗啡暴露量预计会增加约5%。在严重肝损伤人群中，预计吗啡暴露量也会有类似的增加，增幅约为10%。虽然这些预测的吗啡暴露量增加低于美国食品药品监督管理局的临界值（增加1.25倍），但吗啡治疗指数较窄，暴露量增加5-10%可能具有临床相关性。需要进一步的临床研究来全面表征与吗啡相关的DDIs的临床相关性。
