Cannabidiol metabolism in vitro : the role of antiseizure medications and CYP2C19 genotypes
Year: 2025
Type: article
Abstract: 1. Cannabidiol (CBD) can be used as add-on antiseizure medication.We aimed to investigate CBD depletion kinetics when combined with antiseizure medications, further the effect of intermediate-activity CYP2C19 genotype on CBD metabolism.2. CBD depletion in pooled human liver microsomes was studied at varying concentrations (400-6000 nM) in the absence and presence of valproic acid, clobazam, stiripentol and topiramate.In addition, CBD metabolism in HLMs from CYP2C19 *1/*2 or *1/*4 donors was investigated.Incubation samples were analysed for CBD and metabolites 7-OH-CBD and 7-COOH-CBD using LC-MS/MS.CBD in vitro intrinsic clearance (CL int ) was calculated using estimated V max and K m values and further extrapolated to in vivo CL int .3. In vitro CL int values were reduced by approximately 25-85% in the presence of antiseizure medication(s) with the largest effect observed for the combination of four antiseizure drugs.There was no discernible difference for HLMs with CYP2C19 *1/*2 or *1/*4 genotype.Increases in CBD depletion half-lives at higher concentrations indicated substrate inhibition and/or metabolic saturation.4. Projected decreases in CBD CL int values when combined with several antiseizure medications simultaneously suggest a possibility drug-drug interaction potential to clinical relevance.A 1.3-to 4.8-fold increased exposure to unbound systemic CBD concentrations was predicted when combined with these antiseizure medications.
Source: Xenobiotica
Institution: University of Gothenburg
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4410030459