Cannabidiol metabolism in vitro: the role of antiseizure medications and CYP2C19 genotypes.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2025-03-01 Epub Date: 2025-05-10 DOI:10.1080/00498254.2025.2498696

Nattapon Jaisupa, Michael Ashton, Sofia Birgersson

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引用次数: 0

Abstract

Cannabidiol (CBD) can be used as add-on antiseizure medication. We aimed to investigate CBD depletion kinetics when combined with antiseizure medications, further the effect of intermediate-activity CYP2C19 genotype on CBD metabolism.CBD depletion in pooled human liver microsomes (HLMs) was studied at varying concentrations (400-6000 nM) in the absence and presence of valproic acid, clobazam, stiripentol and topiramate. In addition, CBD metabolism in HLMs from CYP2C19 *1/*2 or *1/*4 donors was investigated. Incubation samples were analysed for CBD and metabolites 7-OH-CBD and 7-COOH-CBD using LC-MS/MS. CBD in vitro intrinsic clearance (CL_int) was calculated using estimated V_max and K_m values and further extrapolated to in vivo CL_int.In vitro CL_int values were reduced by approximately 25-85% in the presence of antiseizure medication(s) with the largest effect observed for the combination of four antiseizure drugs. There was no discernible difference for HLMs with CYP2C19 *1/*2 or *1/*4 genotype. Increases in CBD depletion half-lives at higher concentrations indicated substrate inhibition and/or metabolic saturation.Projected decreases in CBD CL_int values when combined with several antiseizure medications suggest a potential for clinically relevant drug-drug interactions. A 1.3- to 4.8-fold increased exposure to unbound systemic CBD concentrations was predicted when combined with these antiseizure medications.

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大麻二酚体外代谢：抗癫痫药物和CYP2C19基因型的作用。

1. 大麻二酚（CBD）可以作为附加的抗癫痫药物。我们的目的是研究CBD与抗癫痫药物联合使用时的耗竭动力学，并进一步研究中活性CYP2C19基因型对CBD代谢的影响。在不含丙戊酸、氯巴唑、斯立哌醇和托吡酯的情况下，研究了不同浓度（400-6000 nM）的混合人肝微粒体（HLMs）中CBD的耗竭。此外，研究了CYP2C19 *1/*2或*1/*4供者HLMs的CBD代谢。利用LC-MS/MS分析培养样品中CBD及其代谢物7-OH-CBD和7-COOH-CBD。使用估计的Vmax和Km值计算CBD体外固有清除率（CLint），并进一步外推到体内CLint。在抗癫痫药物的存在下，体外CLint值降低了约25-85%，其中四种抗癫痫药物联合使用的效果最大。CYP2C19 *1/*2或*1/*4基因型的HLMs无明显差异。高浓度CBD消耗半衰期的增加表明底物抑制和/或代谢饱和。当与几种抗癫痫药物联合使用时，预计CBD CLint值会下降，这表明可能存在与临床相关的药物-药物相互作用。当与这些抗癫痫药物联合使用时，预计未结合的全身CBD浓度增加1.3至4.8倍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology