Nonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats

Abstract

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 50 mg/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 50 mg/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, 13 C-erythromycin was orally administered following administration of either NE (without CBD), as a control, or CBD-NE at 1, 10, and 50 mg/kg, and 13 C-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 10 mg/kg. The AUC and maximum plasma concentration (C max) 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 13 C-breath response, the metabolism of 13 C-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.

Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

“…In rats, 24 studies reported anxiety outcomes (Almeida et al, 2013;Espejo-Porras et al, 2013;Gáll et al, 2020;Gazarini et al, 2014;Guimarães et al, 1994;Hložek et al, 2017;Javadi-Paydar et al, 2019;Jurkus et al, 2016;Kajero et al, 2020;Karniol et al, 1974;Lemos et al, 2010;Mahmud et al, 2017;Malone et al, 2009;Martín-González et al, 2018;Moreira et al, 2006;Murkar et al, 2019;O'Brien et al, 2013;Resstel et al, 2006;Rock et al, 2017;Shallcross et al, 2019;Shoval et al, 2016;Song et al, 2016;Stern et al, 2012Stern et al, , 2015 and 10 studies reported only PK outcomes (Cherniakov et al, 2017;Deiana et al, 2012;Feng et al, 2021;Izgelov et al, 2020bIzgelov et al, , 2020cIzgelov et al, , 2020dNagao et al, 2020;Paudel et al, 2010;Xu et al, 2019;Zgair et al, 2016). In one study, both types of outcomes were reported (Hložek et al, 2017).…”

Feature-Based Molecular Network-Assisted Cannabinoid and Flavonoid Profiling of Cannabis sativa Leaves and Their Antioxidant Properties

“…The double-edged-sword-like pharmacological effects have been confirmed from the phytocannabinoids, which were enriched in the female inflorescence. With the discovery of medicinal uses of cannabidiol (CBD) [ 2 , 3 ] and the development of related drugs in recent years, some countries and regions such as the United States and Canada have implemented Cannabis species legalization policies.…”

Toxicological safety assessment of HempChoice® hemp oil extract; a proprietary extract consisting of a high concentration of cannabidiol (CBD) in addition to other phytocannabinoids and terpenes derived from Cannabis sativaL

“…Reviews and research reports in humans and laboratory animals have described the in vivo and in vitro toxicologic effects of CBD-containing hemp extracts at various dosage levels [ 13 , [18] , [19] , [20] , [21] , [22] ]. The authors concluded that these studies generally support the conclusion that CBD-containing hemp extracts are safe for humans inclusive of intermittent chronic use.…”