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Simultaneous quantitative determination of 19 new psychoactive substances in human plasma and metabolic profiles of 25N-NBOMe and 25E-NBOMe in human liver microsomes

Title
Simultaneous quantitative determination of 19 new psychoactive substances in human plasma and metabolic profiles of 25N-NBOMe and 25E-NBOMe in human liver microsomes
Authors
홍진
Issue Date
2019
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
신윤용
Abstract
According to the World Drug Report 2018, hundreds of new psychoactive substances (NPS) have been synthesized and added to the established synthetic drug market for amphetamine-type substances. Health care provider and scientist on responding to NPS has posed a major challenge to drug policy. The purpose of this study is for simultaneous quantitative analytic method of 19 hallucinogenic NPS derivatives in human plasma using liquid chromatography tandem mass spectrometry. In addition, metabolic profile determination of 2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine(25N-NBOMe) and 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe) in human liver microsomes by liquid chromatography-quadrupole time-of-flight mass spectrometry was performed. To determine simultaneous quantitative analysis of 19 NPS(25H-NBOMe, 25B-NBF, 25CNBOH, 25C-NBF, 25I-NBF, 25I-NBOH, 25B-NBOMe, 25N-NBOMe, 25E-NBOMe, 4-methyl-2, 5,beta-trimethoxyphen-ethylamine known as BOD, Methallylescaline, Allylescaline, Flubromazepam, piperidine-based Desoxypipradol also known as 2-DPMP, Mexedrone of Methcathinone class, Synthacaine of synthetic cocaine, 2-MeO-diphenidine of diarylalkylamine class, ORG27569 of synthetic cannabinoids and W-18), human plasma samples were pre-treated using solid-phase extraction. Separation was achieved on a C18 column under gradient elution using a mobile phase containing 0.1% formic acid in acetonitrile and 0.1% formic acid in water at a flow rate of 0.3mL/min. Mass detection was performed in the positive ion mode using multiple reaction monitoring. The calibration range was 1 to 100ng/mL for all quantitative analytes, with a correlation coefficient greater than 0.99. The intra- and inter-day precision and accuracy varied from 0.85 to 12.70% and from 92.65 to 110.97%, respectively. The recovery ranged from 14.63 to 117.40%, and the matrix effects ranged from 54.03 to 118.52%. The stability was acceptable in various conditions. The LC-MS/MS method was validated for linearity, accuracy, precision, matrix effects, recovery and stability in accordance with the FDA guidance. In addition, the in vitro metabolism of 25N-NBOMe and 25E-NBOMe were investigated with human liver microsomes, and the reaction mixture was analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry(LC-Q-TOF/MS). Formation of 14 metabolites(M1-M14) of 25N-NBOMe and 22 metabolites(M1-M22) of 25E-NBOMe were yielded with incubation of 25N-NBOMe and 25E-NBOMe in human liver microsomes in the presence of NADPH, respectively. The metabolic profiles of 25N-NBOMe and 25E-NBOMe were structurally determined on the basis of the MS/MS fragmentation patterns. The biotransformations included hydroxylation, O-demethylation, N-dealkylation, nitro reduction, dehydrogenation carbonylation, and combinations thereof. Hydroxyl metabolite was the most abundant compound after the phase I process. It is considered that these results of simultaneous quantitative determination of 19 NPS and metabolic profile of 25N-NBOMe and 25E-NBOMe will be globally helpful information to health care provider as well as scientists in drug enforcement agencies.;신종 마약류의 경우 중독성, 환각 증세, 공격성 있는 물질이 대부분으로 최근 페이스북, 소셜 네트워크 서비스 등 인터넷을 통한 개인적구매가 손쉬워지면서 오남용 사례들이 급증하고 있다. 이로 인한 심각한 범죄가 증가함에 따라 사회적 문제를 예방하고 확산방지를 위해 과학적 근거 제공이 절실히 요구되고 있다. 이에 본 연구에서는 19종 신종마약류, 25H-NBOMe, 25B-NBF, 25CNBOH, 25C-NBF, 25I-NBF, 25I-NBOH, 25B-NBOMe, 25N-NBOMe, 25E-NBOMe, BOD, Methallylescaline, Allylescaline, 2-DPMP, Mexedrone, Synthacaine, 2-MeO-diphenidine, ORG27569, W-18 및 Flubromazepam을 동시에 분석할 수 있는 분석법 및 25N-NBOMe와 25E-NBOMe의 대사체 규명하였다. 생체시료인 혈장에서 신종 마약류 19종에 대한 동시분석법을 확립하고자 직선성, 정확성, 정밀성, 안정성 조건을 확립하였다. 이 중 신종마약류 2종, 25N-NBOMe, 25E-NBOMe에 대해서는 사람 간 소포체를 이용해 대사시킨 후 각 대사반응물의 LC-HRMS 분석조건을 확립하고 accurate mass 측정한 후 대사경로 및 대사체를 확인한 결과, 조사된 대사체로는 25N-NBOMe의 경우는 N-dealkylation, O-demethyl-ation, hydroxylation, desaturation, carbonylation, nitro reduction 이며, 25E-NBOMe의 경우는 N-dealkylation, O-demethylation, desaturation, hydroxylation, di-hydroxylation 과정을 통해 대사됨을 알 수 있었다. 이러한 연구결과는 실제 신종 마약 검출을 위해 활용될 수 있을 뿐만 아니라 비슷한 구조의 신종 마약 검출법 개발에 활용 가능한바 마약류 단속을 실행하는 정부 행정기관 및 연구 전문가에게 유익한 새로운 정보로 제공 될 수 있을 것으로 사료된다.
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