Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Oct;393(10):1871-1886. doi: 10.1007/s00210-020-01878-2. Epub 2020 May 19.
Carbamazepine (CBZ) is mainly metabolized by CYP3A4 into carbamazepine-10,11-epoxide (CBZE). Cannabidiol (CBD) is a potent inhibitor of the CYP3A family. The aim of this study is to determine the effect of acute and chronic administration of CBD on the pharmacokinetics of CBZ and CBZE. Male SD rats were assigned into four acute and four chronic groups: control (CBZ only), positive control (ketoconazole), low-dose cannabidiol (l-CBD), and high-dose cannabidiol (h-CBD). Acute CBD groups were administered a single dose of CBD, while chronic CBD groups were given multiple doses of CBD for 14 days (q.d.) before CBZ administration. Plasma samples had been collected and analyzed for CBZ and CBZE, then their noncompartmental pharmacokinetic parameters before and after CBD administration were determined. The co-administration of a single l-CBD has significantly increased CBZ's [Formula: see text] by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in C by 31.8%. Acute h-CBD caused similar effects on CBZ's [Formula: see text] with 40.4% significant decrease in CBZE's C, when compared to the control. Chronic h-CBD caused a significant decrease in CBZ's C and [Formula: see text] by 75.3% and 65.7%, respectively. Besides, [Formula: see text] and C of CBZE significantly decreased by 75.3% and 78.3%, respectively. These results demonstrated that the pharmacokinetics of CBZ and CBZE had been significantly affected by CBD. When CBD has been administered as a single dose, the effect is believed to be mainly caused by the inhibition of CBZ metabolism through CYP3A. The effect of chronic administration of CBD probably includes kinetic pathways other than the inhibition of CYP3A-dependent pathways. Graphical abstract.
卡马西平（CBZ）主要通过 CYP3A4 代谢为卡马西平-10,11-环氧化物（CBZE）。大麻二酚（CBD）是 CYP3A 家族的一种有效抑制剂。本研究旨在确定 CBD 的急性和慢性给药对 CBZ 和 CBZE 药代动力学的影响。雄性 SD 大鼠被分为四组急性组和四组慢性组：对照组（仅 CBZ）、阳性对照组（酮康唑）、低剂量大麻二酚（l-CBD）和高剂量大麻二酚（h-CBD）。急性 CBD 组给予单次 CBD 给药，而慢性 CBD 组在给予 CBZ 前给予 14 天（qd）的多次 CBD 给药。收集并分析了血浆样本以检测 CBZ 和 CBZE，然后确定了 CBD 给药前后的非隔室药代动力学参数。单次 l-CBD 的联合给药显著增加了 CBZ 的 [Formula: see text] 53.1%。此外，CBZE 动力学显示 C 降低了 31.8%。与对照组相比，急性 h-CBD 导致 CBZ 的 [Formula: see text] 相似，CBZE 的 C 降低了 40.4%。慢性 h-CBD 导致 CBZ 的 C 和 [Formula: see text] 分别显著降低了 75.3%和 65.7%。此外，CBZE 的 [Formula: see text] 和 C 分别显著降低了 75.3%和 78.3%。这些结果表明 CBD 显著影响了 CBZ 和 CBZE 的药代动力学。当 CBD 作为单次剂量给药时，其作用被认为主要是通过 CYP3A 抑制 CBZ 代谢引起的。CBD 慢性给药的作用可能包括除了抑制 CYP3A 依赖性途径之外的动力学途径。
