The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats
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ORIGINAL ARTICLE
The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats Ruba S. Darweesh 1
&
Tareq N. Khamis 1 & Tamam El-Elimat 2
Received: 16 December 2019 / Accepted: 17 April 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 AUC∞0 by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in Cmax by 31.8%. Acute h-CBD caused similar effects on CBZ’s AUC∞0 with 40.4% significant decrease in CBZE’s Cmax, when compared to the control. Chronic h-CBD caused a significant decrease in CBZ’s Cmax and AUC∞0 by 75.3% and 65.7%, respectively. Besides, AUC∞0 and Cmax 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.
Keywords Cannabidiol . Carbamazepine . Carbamazepine-10,11-epoxide . Drug–drug interactions . Pharmacokinetics . CYP3A Abbreviations AEDs Antiepileptic drugs ∞ AUC0 Total area under the curve AUMC∞0 Total area under the first moment curve CBZ Carbamazepine CBZE Carbamazepine-10,11-epoxide Cmax Maximum plasma concentration CYP Cytochrome P450 DI Deionized DMSO Dimethyl sulfoxide
* Ruba S. Darweesh [email protected] 1
Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
2
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
F h-CBD HLMs IC50 IG IP KTZ l-CBD LLOQ MRT PEG QC QCH QCL QCM THC tmax t0.5 Vz/F
Bioavailability High dose of cannabidiol Human liver microsomes Half maximal inhibitory concentration Intragastric Intraperitoneal Ketoconazole Low dose of cannabidiol Lower limit of quantification Mean residence time Polyethylene glycol Quality control High-quality control Low-quality control Medium-quality control
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