Open AccessNonlinear Disposition and Metabolic Interactions of Cannabidiol Through CYP3A Inhibition In Vivo in Rats
Author(s) -
Michiru Nagao,
Yukako Nakano,
Masataka Tajima,
Erika Sugiyama,
Vilasinee Hirunpanich Sato,
Makoto Inada,
Hitoshi Sato
Publication year - 2020
Publication title -
cannabis and cannabinoid research
Language(s) - English
Resource type - Journals
eISSN - 2578-5125
pISSN - 2378-8763
DOI - 10.1089/can.2019.0098
Subject(s) - cannabidiol , pharmacology , pharmacokinetics , ketoconazole , cmax , chemistry , oral administration , cyp3a , in vivo , area under the curve , medicine , metabolism , cytochrome p450 , biochemistry , biology , cannabis , antifungal , microbiology and biotechnology , dermatology , psychiatry
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 dose-proportional 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 dose-dependent drug interactions should be considered for CBD.