کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
7626957 | 1494584 | 2018 | 30 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification of metabolites of MDR-1339, an inhibitor of β-amyloid protein aggregation, and kinetic characterization of the major metabolites in rats
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کلمات کلیدی
EPILQCMQCReaction phenotypingPEG400RLMAUClastAUCinfHQCIDAtmaxEMSMRMCyPMRTNADPHDMSO - DMSOt1/2 - t1 / 2internal standard - استاندارد داخلیenhanced product ion scan - افزایش اسکن یون محصولcollision energy - انرژی برخوردAlzheimer’s disease - بیماری آلزایمرDimethyl sulfoxide - دیمتیل سولفواکسیدCytochrome P450 - سیتوکروم پی۴۵۰Metabolite identification - شناسایی متابولیتMean residence time - میانگین زمان اقامتRat liver microsomes - میکروسوم های کبدی موشmultiple reaction monitoring - نظارت چندگانه چندگانهnicotinamide adenine dinucleotide phosphate-oxidase - نیکوتین آمید آدنین دیونوکلئوتید فسفات اکسیدازPolyethylene glycol 400 - پلی اتیلن گلیکول 400Information-Dependent Acquisition - کسب اطلاعات وابسته
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We previously reported that MDR-1339, an inhibitor of β-amyloid protein aggregation, was likely to be eliminated by biotransformation in rats. The objective of this study was to determine the chemical identity of metabolites derived from this aggregate inhibitor and to characterize the kinetics of formation of these metabolites in rats. Using high performance liquid chromatography coupled with mass spectrometry with a hybrid triple quadrupole-linear ion trap, 7 metabolites and 1 potential metabolic intermediate were identified in RLM incubations containing MDR-1339. In addition to these, 3 glucuronide metabolites were detected in urine samples from rats receiving a 10â¯mg/kg oral dose of MDR-1339. When the kinetics of the formation of two major metabolites, M1 and M2, were analyzed assuming simple Michaelis-Menten kinetics, the Vmax and Km values were found to be 0.459â¯Â±â¯0.0196 nmol/min/mg protein and 28.3â¯Â±â¯3.07â¯Î¼M for M1, and 0.101â¯Â±â¯0.00537 nmol/min/mg protein and 14.7â¯Â±â¯2.37â¯Î¼M for M2, respectively. When chemically synthesized M1 and M2 were individually administered to rats intravenously at the dose of 5â¯mg/kg respectively, the volume of distribution and elimination clearance were determined to be 4590â¯Â±â¯709â¯mL/kg and 68.4â¯Â±â¯5.60â¯mL/min/kg for M1 and 15300â¯Â±â¯8110â¯mL/kg and 98.0â¯Â±â¯19.5â¯mL/min/kg for M2, respectively. When MDR-1339 was intravenously administered to rats at a dose of 5â¯mg/kg, the parent drug and M1 were readily detected for periods of up to 6â¯h after the administration, but M2 was observed only from 2 to 4â¯h. A standard moment analysis indicates that the formation clearance of M1 is 6.01â¯mL/min/kg, suggesting that 19.7% of the MDR-1339 dose was eliminated in rats. These observations indicate that the hepatic biotransformation of MDR-1339 results in the formation of at least 10 metabolites and that M1 is the major metabolite derived from this aggregation inhibitor in rats.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 151, 20 March 2018, Pages 61-70
Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 151, 20 March 2018, Pages 61-70
نویسندگان
Jun-Hyeng Son, Yoo-Seong Jeong, Jong-Hwa Lee, Min-Soo Kim, Kyeong-Ryoon Lee, Chang-Koo Shim, Young Ho Kim, Suk-Jae Chung,