Nagao Michiru, Nakano Yukako, Tajima Masataka, Sugiyama Erika, Sato Vilasinee Hirunpanich, Inada Makoto, Sato Hitoshi
Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, Tokyo, Japan.
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Cannabis Cannabinoid Res. 2020 Dec 15;5(4):318-325. doi: 10.1089/can.2019.0098. eCollection 2020.
Cannabidiol (CBD) is known to affect the pharmacokinetics of other drugs through metabolic inhibition of CYP2C19 and CYP3A4. However, there is a lack of evidence for such drug interactions. Therefore, we investigated the saturability of CBD metabolism and CBD-drug interactions through inhibition of CYP3A . 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, 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 C-breath response was measured by using an infrared analyzer. 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) 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 C-breath response, the metabolism of C-erythromycin was shown to be inhibited by CBD at doses of 10 and 50 mg/kg, but not at 1 mg/kg. Nonlinear disposition and CYP-mediated drug interactions of CBD at doses exceeding 10 mg/kg were demonstrated for the first time in rats. Given the present results, it is proposed that caution for dose-dependent drug interactions should be considered for CBD.
已知大麻二酚（CBD）可通过对细胞色素P450 2C19（CYP2C19）和细胞色素P450 3A4（CYP3A4）的代谢抑制作用来影响其他药物的药代动力学。然而，缺乏此类药物相互作用的证据。因此，我们通过抑制CYP3A来研究CBD代谢的饱和性以及CBD与药物的相互作用。将CBD纳米乳剂（CBD-NE）以5、10、25和50mg/kg的剂量口服给予大鼠，并使用液相色谱-串联质谱法（LC-MS/MS）测量CBD的血浆浓度，以研究CBD暴露（曲线下面积[AUC]）的剂量依赖性。为了研究CYP3A抑制剂对CBD药代动力学的影响，在以10和50mg/kg的剂量口服给予CBD-NE之前，给大鼠口服50mg/kg酮康唑（KCZ，一种强效CYP3A抑制剂）进行预处理，并使用LC-MS/MS测量CBD的血浆浓度。此外，在给予作为对照的NE（不含CBD）或1、10和50mg/kg的CBD-NE之后，口服给予C-红霉素，并使用红外分析仪测量C-呼气反应。给大鼠给予不同剂量的纳米乳化CBD制剂后，CBD的暴露量（即根据血浆浓度-时间曲线计算的AUC）以大于剂量比例的方式增加，尤其是在剂量高于10mg/kg时。联合给予KCZ后，口服CBD-NE（10mg/kg）后CBD的AUC和最大血浆浓度（Cmax）增加了约三倍。此外，根据CBD引起的C-呼气反应变化，在10和50mg/kg剂量下，CBD可抑制C-红霉素的代谢，但在1mg/kg剂量下则无此作用。首次在大鼠中证明了超过10mg/kg剂量的CBD存在非线性处置和CYP介导的药物相互作用。鉴于目前的结果，建议对CBD的剂量依赖性药物相互作用应予以谨慎考虑。
