Cannabidiol metabolism <i>in vitro</i> : the role of antiseizure medications and CYP2C19 genotypes

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.CBD depletion in pooled human liver microsomes (HLMs) 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 <i>*1/*2</i> or <i>*1/*4</i> donors was investigated. Incubation samples were analysed for CBD and metabolites 7-OH-CBD and 7-COOH-CBD using LC-MS/MS. CBD <i>in vitro</i> intrinsic clearance (CL_int) was calculated using estimated V_max and K_m values and further extrapolated to <i>in vivo</i> CL_int.<i>In vitro</i> 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 <i>*1/*2</i> or <i>*1/*4</i> genotype. Increases in CBD depletion half-lives at higher concentrations indicated substrate inhibition and/or metabolic saturation.Projected decreases in CBD CL_int values when combined with several antiseizure medications suggest a potential for clinically relevant drug-drug interactions. A 1.3- to 4.8-fold increased exposure to unbound systemic CBD concentrations was predicted when combined with these antiseizure medications.