Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., M.K.L., J.D.U.); Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.F.P.); and Center of Excellence for Natural Product Drug Interaction Research (M.F.P., J.D.U.).
Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., M.K.L., J.D.U.); Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.F.P.); and Center of Excellence for Natural Product Drug Interaction Research (M.F.P., J.D.U.)
Drug Metab Dispos. 2023 Jun;51(6):743-752. doi: 10.1124/dmd.122.001128. Epub 2023 Mar 27.
Cannabidiol (CBD) is available as a prescription oral drug that is indicated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Accordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions. Such interactions can be predicted in healthy and hepatically-impaired (HI) adults and in children through physiologically based pharmacokinetic (PBPK) modeling and simulation. These PBPK models must be populated with CBD-specific parameters, including the enzymes that metabolize CBD in adults. In vitro reaction phenotyping experiments showed that UDP-glucuronosyltransferases (UGTs, 80%), particularly UGT2B7 (64%), were the major contributors to CBD metabolism in adult human liver microsomes. Among the cytochrome P450s (CYPs) tested, CYP2C19 (5.7%) and CYP3A (6.5%) were the major CYPs responsible for CBD metabolism. Using these and other physicochemical parameters, a CBD PBPK model was developed and validated for healthy adults. This model was then extended to predict CBD systemic exposure in HI adults and children. Our PBPK model successfully predicted CBD systemic exposure in both populations within 0.5- to 2-fold of the observed values. In conclusion, we developed and validated a PBPK model to predict CBD systemic exposure in healthy and HI adults and children. This model can be used to predict CBD-drug or CBD-drug-disease interactions in these populations. SIGNIFICANCE STATEMENT: Our PBPK model successfully predicted CBD systemic exposure in healthy and hepatically-impaired adults, as well as children with epilepsy. This model could be used in the future to predict CBD-drug or CBD-drug-disease interactions in these special populations.
大麻二酚 (CBD) 可作为处方口服药物使用，用于治疗儿童和成人的某些类型癫痫。CBD 也可在柜台上购买，用于自行治疗各种其他疾病，包括疼痛、焦虑和失眠。因此，CBD 可能与其他药物一起使用，从而导致可能的 CBD 药物相互作用。这些相互作用可以通过生理基于药代动力学 (PBPK) 建模和模拟在健康和肝损伤 (HI) 成年人以及儿童中进行预测。这些 PBPK 模型必须用 CBD 特异性参数填充，包括在成年人中代谢 CBD 的酶。体外反应表型实验表明，尿苷二磷酸葡萄糖醛酸转移酶 (UGTs，80%），特别是 UGT2B7（64%），是成人肝微粒体中 CBD 代谢的主要贡献者。在所测试的细胞色素 P450 中（CYP），CYP2C19（5.7%）和 CYP3A（6.5%）是负责 CBD 代谢的主要 CYP。使用这些和其他物理化学参数，开发并验证了用于健康成年人的 CBD PBPK 模型。然后，将该模型扩展到预测 HI 成年人和儿童的 CBD 全身暴露。我们的 PBPK 模型成功地预测了这两个群体中 CBD 全身暴露的情况，预测值与观察值相差 0.5 至 2 倍。总之，我们开发并验证了一种 PBPK 模型，用于预测健康和 HI 成年人和儿童的 CBD 全身暴露。该模型可用于预测这些人群中的 CBD 药物或 CBD 药物疾病相互作用。意义陈述：我们的 PBPK 模型成功预测了健康和肝损伤成年人以及癫痫儿童的 CBD 全身暴露。该模型可用于预测未来这些特殊人群中的 CBD 药物或 CBD 药物疾病相互作用。
