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; Hitoshi Sato

doi:10.1089/can.2019.0098

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

Cannabis Cannabinoid Res. 2020 Dec 15;5(4):318-325. doi: 10.1089/can.2019.0098. eCollection 2020.

Authors

Michiru Nagao¹, Yukako Nakano¹, Masataka Tajima¹, Erika Sugiyama¹, Vilasinee Hirunpanich Sato², Makoto Inada³, Hitoshi Sato¹

Affiliations

¹ Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, Tokyo, Japan.
² Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
³ Development Department Diagnostic Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.

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, ¹³C-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 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 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 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 dose-dependent drug interactions should be considered for CBD.

Keywords: CYP3A; cannabidiol; drug interactions; metabolism; nonlinear pharmacokinetics; rats.