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dc.contributor.authorWinefield, Robert D.
dc.contributor.authorHeemskerk, Anthonius A. M.
dc.contributor.authorKaul, Swetha
dc.contributor.authorWilliams, Todd D.
dc.contributor.authorCaspers, Michael J.
dc.contributor.authorPrisinzano, Thomas E.
dc.contributor.authorMcCance-Katz, Elinore F.
dc.contributor.authorLunte, Craig E.
dc.contributor.authorFaiman, Morris D.
dc.date.accessioned2017-05-25T18:33:32Z
dc.date.available2017-05-25T18:33:32Z
dc.date.issued2015-03-25
dc.identifier.citationWinefield, R. D., Heemskerk, A. A. M., Kaul, S., Williams, T. D., Caspers, M. J., Prisinzano, T. E., … Faiman, M. D. (2015). N-Acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in RAT and human plasma after disulfiram administration. Journal of Pharmaceutical and Biomedical Analysis, 107, 518–525. http://doi.org/10.1016/j.jpba.2015.01.036en_US
dc.identifier.urihttp://hdl.handle.net/1808/24309
dc.description.abstractDisulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291 > 128) is easily separable from DETC-NAC (MIM: 263 > 100) on C18 RP media with a methanol gradient. The method's linear range is 0.5–500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6 h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95–105) is discussed.en_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectDisulfiramen_US
dc.subjectN-acetyl-S-(N,N-diethylcarbamoyl) cysteineen_US
dc.subjectDETC-NACen_US
dc.subjectCarbamathioneen_US
dc.subjectSubstance abuse disordersen_US
dc.subjectMercapturate pathwayen_US
dc.titleN-Acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in RAT and human plasma after disulfiram administrationen_US
dc.typeArticleen_US
kusw.kuauthorWinefield, Robert D.
kusw.kuauthorHeemskerk, Anthonius A.M.
kusw.kuauthorKaul, Swetha
kusw.kuauthorWilliams, Todd D.
kusw.kuauthorCaspers, Michael J.
kusw.kuauthorPrisinzano, Thomas E.
kusw.kuauthorLunte, Craig E.
kusw.kuauthorFaiman, Morris D.
kusw.kudepartmentPharmaceutical Chemistryen_US
dc.identifier.doi10.1016/j.jpba.2015.01.036en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-0944-5407
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC4410022en_US
dc.rights.accessrightsopenAccess


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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.