Qian Lixuan, Zhang Tao, Dinh Jean, Paine Mary F, Zhou Zhu
Department of Chemistry, York College, City University of New York, New York, USA.
Department of Pharmaceutical Sciences, Binghamton University, the State University of New York, Vestal, New York, USA.
Clin Transl Sci. 2025 Jan;18(1):e70119. doi: 10.1111/cts.70119.
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 (C) of CBD and THC from the verification dataset. Predicted AUC and C 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 C 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.
两种研究最为广泛的大麻素，即大麻二酚（CBD）和Δ9-四氢大麻酚（THC），被用于多种病症。THC主要通过细胞色素P450（CYPs）代谢消除，而CBD则通过CYPs和尿苷二磷酸葡萄糖醛酸转移酶（UGTs）共同代谢消除。这些酶对大麻素代谢的相对贡献在各项研究中结果不一。基于生理学的药代动力学（PBPK）模型针对CBD和THC以及涉及以CBD或THC为受试药物的药物相互作用研究得以开发和验证，以改进对这些相对贡献的估计。首先，从文献中获取或优化CBD、THC及其代谢物（7-羟基-CBD、11-羟基-THC和11-羧基-THC）的理化和药代动力学参数。其次，建立静脉注射后CBD和THC的PBPK基础模型。第三，从静脉注射模型开始，建立口服和口腔黏膜喷雾给药后CBD以及口服、吸入和口腔黏膜喷雾给药后THC的吸收模型。完整模型很好地拟合了验证数据集中CBD和THC的浓度-时间曲线下面积（AUC）和峰浓度（C）。CBD和7-羟基-CBD的预测AUC和C在观测数据的两倍范围内。对于THC、11-羟基-THC和11-羧基-THC，预测AUC值分别有100%、100%和83%在观测值的两倍范围内；预测C值分别有100%、92%和94%在观测值的两倍范围内。经过验证的模型可用于帮助满足关键的公共卫生需求，包括评估涉及CBD和THC的潜在药物相互作用风险。
