Cannabidiol metabolism in vitro : the role of antiseizure medications and CYP2C19 genotypes

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 (CLint) was calculated using estimated Vmax and Km values and further extrapolated to in vivo CLint.3. In vitro CLint 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 CLint 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.