Simultaneous analysis of diphenylmethoxyacetic acid,a metabolite of diphenhydramine,and its deuterium-labeled stable isotope analog in ovine plasma and urine |
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| Affiliation: | 1. Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada;2. Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada;3. Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada;4. Department of Obstetrics and Gynecology, Faculty of Medicine, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada;5. Department of Anaesthesia, Faculty of Medicine, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada;1. Zhejiang University of Technology, Hangzhou 310004, China;2. Zhejiang Institute for Food and Drug Control, Hangzhou 310052, China;1. UMR 6538 Laboratoire Géosciences Océan, Institut Universitaire Européen de la Mer, Place Nicolas Copernic, 29280, Plouzané, France;2. IFREMER, Laboratoire Géodynamique et enregistrements Sédimentaires, BP70, 29280, Plouzané, France;3. Earth Observatory Singapore, Nanyang Technological University, 639798, Singapore;4. SEDISOR, Institut Universitaire Européen de la Mer, Place Nicolas Copernic, 29280, Plouzané, France;1. Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China;2. Department of Radiology, Qingdao Municipal Hospital, Qingdao, Shandong, China;1. Department of Industrial Engineering—Federal University of Rio Grande do Sul, Av. Osvaldo Aranha, 99-5° andar, 90035-190 Porto Alegre, RS, Brazil;2. Rio Grande do Sul Technical and Scientifical Division, Brazilian Federal Police, Avenida Ipiranga 1365, 90160-093 Porto Alegre, RS, Brazil;3. Department of Pharmacy, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, 90610-000 Porto Alegre, RS, Brazil;1. Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;2. Department of Bioanalysis and Drugs Analysis, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland |
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| Abstract: | Diphenylmethoxyacetic acid (DPMA) is a major metabolite of diphenhydramine in monkeys, dogs, and humans. The metabolic fate of diphenhydramine (DPHM) in sheep is not yet well understood; however, preliminary studies have demonstrated the presence of DPMA in the plasma and urine of sheep following an intravenous bolus of DPHM. Our current studies employ the simultaneous intravenous co-administration of DPHM and the stable isotope analog of DPHM to investigate the pharmacokinetics of DPHM in sheep. In these studies, in order to investigate the pharmacokinetics of the DPMA metabolite, measurement of both unlabeled and stable-isotope labeled DPMA is required. Thus, a stable isotope analog of DPMA ([2H10]DPMA) was synthesized, characterized, and purified for use as an analytical standard. The quantitative method for the gas chromatography—electron-impact mass spectrometry (GC—EI-MS) analysis of DPMA and [2H10]DPMA used a single step liquid-liquid extraction procedure using toluene for sample cleanup. The samples were derivatized with N-methyl-N-(tert.-butyldimethylsilyl) trifluoroacetamide. A 1.0-μl aliquot of the prepared sample was injected into the GC-MS system and quantitated using selected-ion monitoring (SIM). One ion was monitored for each compound, namely, m/z 165 for the internal standard diphenylacetic acid, m/z 183 for DPMA, and m/z 177 for [2H10]DPMA. The ion chromatograms were free from chromatographic peaks co-eluting with the compound of interest. The calibration curve was linear from 2.5 ng/ml (limit of quantitation) to 250.0 ng/ml in both urine and plasma. The intra-day and inter-day variabilities of this assay method were within acceptable limits (below 20% at the limit of quantitation and below 10% at all other concentrations). This method was used to measure the concentration of DPMA and [2H10]DPMA in plasma and urine samples from a ewe in which equimolar amounts of DPHM and [2H10]DPHM were administered by an intravenous bolus dose via the femoral vein. DPMA appeared to persist longer in the plasma and the urine as compared to DPHM. This method is robust and reliable for the quantitation of DPMA and [2H10]DPMA in biological samples obtained from sheep (e.g. plasma and urine). |
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