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. 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.