Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats
Michiru Nagao, Yukako Nakano, Masataka Tajima, Erika Sugiyama, Vilasinee Hirunpanich Sato,
Makoto Inada, and Hitoshi Sato
Cannabis and Cannabinoid Research, 2020, Volume X, Number X, 1-8.
Introduction : Cannabidiol (CBD) is known to affect the pharmacokinetics of other drugs through metabolic inhibition of CYP2C19 and CYP3A4. However, there is a lack of in vivo evidence for such drug interactions. Therefore, we investigated the saturability of CBD metabolism and CBD-drug interactions through inhibition of CYP3A in vivo.
Materials and Methods : A nanoemulsion formulation of CBD (CBD-NE) was orally administered to rats at doses of 5, 10, 25, and 50mg/kg, and plasma concentrations of CBD were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the dose-dependency of CBD exposure (area under the curve [AUC]). To examine the effect of a CYP3A inhibitor on CBD pharmacokinetics, rats were orally pretreated with 50mg/kg ketoconazole (KCZ), a strong CYP3A inhibitor, before oral administration of CBD-NE at doses of 10 and 50 mg/kg, and plasma concentrations of CBD were measured using LC-MS/MS. Moreover, 13C-erythromycin was orally administered following administration of either NE (without CBD), as a control, or CBD-NE at 1, 10, and 50mg/kg, and 13C-breath response was measured by using an infrared analyzer.
Results : After administration of various doses of the nanoemulsified CBD formulation to rats, the exposure of CBD (i.e., the AUC calculated from the plasma concentration–time profile) increased in a greater than doseproportional manner, especially at doses above 10mg/kg. The AUC and maximum plasma concentration (Cmax) of CBD after oral administration of CBD-NE (10 mg/kg) increased approximately three times by the coadministration of KCZ. Moreover, according to the CBD-induced changes of 13C-breath response, the metabolism of 13C-erythromycin was shown to be inhibited by CBD at doses of 10 and 50 mg/kg, but not at 1 mg/kg.
Conclusions : Nonlinear disposition and CYP-mediated drug interactions of CBD at doses exceeding 10 mg/kg were demonstrated for the first time in vivo in rats. Given the present results, it is proposed that caution for dosedependent drug interactions should be considered for CBD.
Keywords : cannabidiol; drug interactions; CYP3A; nonlinear pharmacokinetics; metabolism; rats
Cannabidiol (CBD) is one of the main cannabinoids contained in cannabis plants. The chemical structure
of CBD is similar to that of a psychoactive cannabinoid, D9-tetrahydrocannabinol, whereas CBD has no psychotropic effects.1 CBD modulates the activities of various cellular effectors, including the cannabinoid receptors CB1 and CB2,2 5HT1A receptors,3 l- and d-opioid receptors, 4 TRPV1 cation channels,5 fatty acid amide hydrolase, 5 GPR3/6/12/55,6,7 peroxisome proliferator-activated receptor c,8 and voltage-dependent anion channel 1.9 CBD has been reported to have clinical effects against epilepsy, anxiety, insomnia, and nausea.1,8,10
Many types of CBD formulations have been available in the market, but oil preparations11 are the most popular owing to the water-insoluble nature of CBD. After CBD formulations are orally administered, the intestinal absorption of CBD molecules is limited by their poor solubility. After a proportion of CBD molecules entered into the portal vein, CBD is extensively metabolized in the liver by cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19.1,12
As CBD is not only an inhibitor of CYP3A and CYP2C but also a substrate of these enzymes,1,12,13 saturation of these enzymatic activities may lead to the nonlinear disposition of CBD as well as CBD-related drug interactions. Therefore, we investigated the correlation between the CBD dose and exposure (i.e., the area under the curve [AUC] of plasma CBD concentrations) and the CBD-drug interactions through alterations in CYP3A activity. For these purposes, we employed a highly absorbable nano-emulsion formulation of CBD (CBD-NE) developed previously in our laboratory14 to eliminate the absorption factors and to focus on themetabolic aspects of CBD.