Disulfiram metabolite S-methyl-N,N-diethylthiocarbamate quantitation in human plasma with reverse phase ultra performance liquid chromatography and mass spectrometry

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• 作者：Jill Hochreiter^a ; Elinore F. McCance-Katz^b ; Jill Lapham^a ; Qing Ma^a ; Gene D. Morse^a ; ^{emorse@buffalo.edu}
• 关键词：Disulfiram ; S-Methyl-N ; N-diethylthiocarbamate ; Ultra performance liquid chromatography ; Mass spectrometry
• 刊名：Journal of Chromatography B ; Analytical Technologies in the Biomedical and Life Sciences
• 出版年：2012
• 期刊代码：124_15700232
• 类别：ch
• 出版时间：15 May, 2012
• 卷：897
• 期：Complete
• 页码：80-84
• 文件大小：505 K

摘要

Disulfiram has been used extensively for alcohol abuse and may have a role in treatment for cocaine addiction. Recent data suggest that disulfiram may also reactivate latent HIV in reservoirs. Disulfiram has complex pharmacokinetics with rapid metabolism to active metabolites, including S-methyl-N,N-diethylthiocarbamate (DET-Me) which is formed from cytochrome P450 (CYP450). Assessing disulfiram in HIV-infected individuals with a CYP450 inducing drug (e.g., efavirenz) or a CYP450 inhibiting drug (e.g., HIV-1 protease inhibitors) requires an assay that can measure a metabolite that is formed directly via CYP450 oxidation. Therefore, an assay to measure concentrations of DET-Me in human plasma was validated. DET-Me and the internal standard, S-ethyldipropylthiocarbamate (EPTC) were separated by isocratic ultra performance liquid chromatography using a Waters Acquity HSS T3 column (2.1 mm 脳 100 mm, 1.8 渭m) and detection via electrospray coupled to a triple quadrupole mass spectrometer. Multiple reaction monitoring in positive mode was used with DET-Me at 148/100 and the internal standard at 190/128 with a linear range of 0.500-50.0 ng/mL with a 5 min run time. Human plasma (500 渭L) was extracted using a solid phase procedure. The interassay variation ranged from 1.86 to 7.74%while the intra assay variation ranged from 3.38 to 5.94%over three days. Representative results are provided from samples collected from subjects receiving daily doses of disulfiram 62.5 mg or 250 mg.