Potential Role of CYP3A4 in Determining In Vivo Exposure to Cannabidiol (CBD) and its Active Metabolite 7-OH-CBD: Evidence from an In Vitro Study

Plasma concentration of cannabidiol (CBD) is a determining factor for its antiseizure efficacy. Since CBD bioavailability decreases with increasing dose, pharmacokinetic drug–drug interactions that reduce its metabolic clearance may represent an alternative strategy to increase systemic exposure without further dose escalation. To investigate in vitro how combinations of antiseizure medications (ASMs) with varying cytochrome P450 (CYP450) inhibitory properties influence the metabolism of CBD and 7-OH-CBD. CBD was incubated with human liver microsomes (HLMs) either alone or in the presence of combinations of two to four commonly prescribed ASMs. These ASMs included valproic acid, clobazam, stiripentol, topiramate, zonisamide, felbamate, perampanel, ethosuximide, rufinamide, lamotrigine, levetiracetam and gabapentin. CBD, 7-OH-CBD and 7-COOH-CBD concentrations were quantified at eight time points by high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Depletion kinetics, metabolite formation rates, and in vitro intrinsic clearance (CL int ) were determined. Ketoconazole, ticlopidine and sulfaphenazole were included as positive controls for CYP3A4, CYP2C19 and CYP2C9 inhibition, respectively. Ketoconazole markedly reduced the CL int of both CBD and its active metabolite, 7-OH-CBD. In contrast, CYP2C19 and CYP2C9 inhibitors produced only minor reductions in CBD CL int . Co-incubation with four CYP3A4-substrate ASMs resulted in a greater reduction in 7-OH-CBD CL int than in CBD CL int . Stiripentol also substantially decreased CBD CL int and markedly reduced the formation of both 7-OH-CBD and 7-COOH-CBD. ASMs with CYP3A4-inhibitory potential may alter systemic exposure to both CBD and its active metabolite, 7-OH-CBD, as demonstrated in vitro. However, co-administration of CBD with CYP3A4-substrate ASMs or CYP2C19 inhibitors is predicted to result in only modest increases in CBD exposure.