吲唑羧酰胺合成大麻素MDMB-CHMINACA的体外I期代谢通过人肝微粒体温育和高分辨率质谱进行。,Drug Testing and Analysis

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吲唑羧酰胺合成大麻素MDMB-CHMINACA的体外I期代谢通过人肝微粒体温育和高分辨率质谱进行。
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2019-06-09 , DOI: 10.1002/dta.2615
Brandon C Presley ₁ , Barry K Logan ₂ , Susan A Jansen-Varnum ₁

Affiliation

合成大麻素在过去十年中激增，已成为主要的公共卫生和分析挑战，对临床和法医界产生了重大影响。吲唑类羧酰胺类合成大麻素尤其猖ramp，由于其对大麻素受体（CB ₁和CB ₂）的高结合亲和力和药效，食用后表现出严重的毒性作用。MDMB-CHMINACA，甲基2- [1-（环己基甲基）-1 H[吲哚-3-羧酰胺基] -3,3-二甲基丁酸酯是该化学类别的化合物，已在法医案件中鉴定出来，并与其他几种合成大麻素在结构上相关。这项研究首次发表了有关有效合成大麻素MDMB-CHMINACA的第一阶段代谢谱的广泛报道。在体外MDMB-CHMINACA的代谢是通过与人肝微粒体温育和高分辨率质谱测定的。获得每种代谢物的前体和碎片的准确质量，质量误差（ppm）和化学式。鉴定出二十七种代谢物，包括十二种代谢物类型。观察到的主要生物转化是羟基化和酯水解。羟基化主要位于环己基甲基（CHM）部分。酯水解后进行另外的生物转化，包括脱氢；单羟基和二羟基化以及酮的形成，每一个都有脱氢作用。鉴定并报告了次要代谢物。作者认为，MDMB-CHMINACA特有的CHM-单羟基化代谢物最适合用于生物分析，以证明该合成大麻素的消费。由于MDMB-CHMINACA的结构相似性以及目前尚无新陈代谢趋势的合成大麻素，因此本研究的结果可作为预测其代谢途径的指南。

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In vitro Phase I metabolism of indazole carboxamide synthetic cannabinoid MDMB-CHMINACA via human liver microsome incubation and high-resolution mass spectrometry.

Synthetic cannabinoids have proliferated over the last decade and have become a major public health and analytical challenge, critically impacting the clinical and forensic communities. Indazole carboxamide class synthetic cannabinoids have been particularly rampant, and exhibit severe toxic effects upon consumption due to their high binding affinity and potency at the cannabinoid receptors (CB₁ and CB₂). MDMB‐CHMINACA, methyl 2‐[1‐(cyclohexylmethyl)‐1H‐indazole‐3‐carboxamido]‐3,3‐dimethylbutanoate, a compound of this chemical class, has been identified in forensic casework and is structurally related to several other synthetic cannabinoids. This study presents the first extensive report on the Phase I metabolic profile of MDMB‐CHMINACA, a potent synthetic cannabinoid. The in vitro metabolism of MDMB‐CHMINACA was determined via incubation with human liver microsomes and high‐resolution mass spectrometry. The accurate masses of precursor and fragments, mass error (ppm), and chemical formula were obtained for each metabolite. Twenty‐seven metabolites were identified, encompassing twelve metabolite types. The major biotransformations observed were hydroxylation and ester hydrolysis. Hydroxylations were located predominantly on the cyclohexylmethyl (CHM) moiety. Ester hydrolysis was followed by additional biotransformations, including dehydrogenation; mono‐ and dihydroxylation and ketone formation, each with dehydrogenation. Minor metabolites were identified and reported. The authors propose that CHM‐monohydroxylated metabolites specific to MDMB‐CHMINACA are the most suitable candidates for implementation into bioanalytical assays to demonstrate consumption of this synthetic cannabinoid. Due to the structural similarity of MDMB‐CHMINACA and currently trending synthetic cannabinoids whose metabolic profiles have not been reported, the results of this study can be used as a guide to predict their metabolic pathways.

更新日期：2019-06-09

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