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The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats

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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 \( {\mathrm{AUC}}_0^{\infty } \) by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in Cmax by 31.8%. Acute h-CBD caused similar effects on CBZ’s \( {\mathrm{AUC}}_0^{\infty } \) 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 \( {\mathrm{AUC}}_0^{\infty } \) by 75.3% and 65.7%, respectively. Besides, \( {\mathrm{AUC}}_0^{\infty } \) 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.

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Abbreviations

AEDs:

Antiepileptic drugs

\( {\mathrm{AUC}}_0^{\infty } \) :

Total area under the curve

\( {\mathrm{AUMC}}_0^{\infty } \) :

Total area under the first moment curve

CBZ:

Carbamazepine

CBZE:

Carbamazepine-10,11-epoxide

C max :

Maximum plasma concentration

CYP:

Cytochrome P450

DI:

Deionized

DMSO:

Dimethyl sulfoxide

F :

Bioavailability

h-CBD:

High dose of cannabidiol

HLMs:

Human liver microsomes

IC50 :

Half maximal inhibitory concentration

IG:

Intragastric

IP:

Intraperitoneal

KTZ:

Ketoconazole

l-CBD:

Low dose of cannabidiol

LLOQ:

Lower limit of quantification

MRT:

Mean residence time

PEG:

Polyethylene glycol

QC:

Quality control

QCH:

High-quality control

QCL:

Low-quality control

QCM:

Medium-quality control

THC:

Tetrahydrocannabinol

t max :

Time to maximum plasma concentration

t 0.5 :

Terminal half-life

Vz/F :

Apparent volume of distribution during the terminal phase

UGT:

Uridine diphosphate glucuronosyl-transferase

λ z :

Terminal elimination rate constant

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Acknowledgments

The authors acknowledge Dr. Masahiro Sakagami of Virginia Commonwealth University, Pharmaceutics Department (VA, USA) for his valuable and helpful discussion about the results. and the Deanship of Research at Jordan University of Science and Technology, Irbid, Jordan, for funding this research (Project no. 0349/2017).

Funding

The authors acknowledge the Deanship of Research at Jordan University of Science and Technology, Irbid, Jordan, for funding this research (Project no. 0349/2017).

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan

    Ruba S. Darweesh & Tareq N. Khamis

  2. Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan

    Tamam El-Elimat

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RSD designed the research. RSD and TNK conducted the experiments, sample analysis, and data processing. TE supervised the development and validation of the analysis method. All the authors contributed to the writing of this manuscript and had read and approved it.

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Correspondence to Ruba S. Darweesh.

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The study protocol was approved by the Animal Care and Use Committee (ACUC) at Jordan University of Science and Technology (JUST), Irbid, Jordan.

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The authors declare that they have no conflicts of interest.

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Darweesh, R.S., Khamis, T.N. & El-Elimat, T. The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1871–1886 (2020). https://doi.org/10.1007/s00210-020-01878-2

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