Abstract | OBJECTIVE:
Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD- clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub- anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.
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Authors | Lyndsey L Anderson, Nathan L Absalom, Sarah V Abelev, Ivan K Low, Peter T Doohan, Lewis J Martin, Mary Chebib, Iain S McGregor, Jonathon C Arnold |
Journal | Epilepsia
(Epilepsia)
Vol. 60
Issue 11
Pg. 2224-2234
(11 2019)
ISSN: 1528-1167 [Electronic] United States |
PMID | 31625159
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy. |
Chemical References |
- Anticonvulsants
- NAV1.1 Voltage-Gated Sodium Channel
- Scn1a protein, mouse
- Cannabidiol
- Clobazam
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Topics |
- Animals
- Anticonvulsants
(administration & dosage, pharmacokinetics)
- Cannabidiol
(administration & dosage, pharmacokinetics)
- Clobazam
(administration & dosage, pharmacokinetics)
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
(methods)
- Drug Interactions
(physiology)
- Drug Therapy, Combination
- Epilepsies, Myoclonic
(drug therapy, genetics, metabolism)
- Humans
- Mice
- Mice, Transgenic
- NAV1.1 Voltage-Gated Sodium Channel
(genetics)
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