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首页> 外文期刊>Journal of pharmaceutical sciences. >Comprehensive quantitative and qualitative liquid chromatography-radioisotope-mass spectrometry analysis for safety testing of tolbutamide metabolites without standard samples.
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Comprehensive quantitative and qualitative liquid chromatography-radioisotope-mass spectrometry analysis for safety testing of tolbutamide metabolites without standard samples.

机译：全面的定量和定性液相色谱-放射性同位素质谱分析法，用于无标准样品的甲苯磺丁酰胺代谢物的安全性测试。

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摘要

Liquid chromatography-radioisotope-mass spectrometry (LC-RI-MS) analysis was used to determine the structures of 12 (four previously unknown) (14) C-tolbutamide (TB) metabolites in rat biological samples (plasma, urine, bile, feces, and microsomes). The four novel metabolites are omega-carboxy TB, hydroxyl TB (HTB)-O-glucuronide, TB-ortho or meta-glutathion, and tolylsulphoaminocarbo-glutathion. In rat plasma, after oral administration of (14) C-TB at therapeutic dose (1 mg/kg) and microdose (1.67 microg/kg), the total RI and six metabolites [HTB, carboxy TB (CTB), M1: desbutyl TB, M2: omega-hydroxyl TB, M3: alpha-hydroxyl TB, and M4: omega-1-hydroxyl TB] were quantified by LC-RI-MS. The plasma concentrations were calculated using their response factors (MS-RI intensity ratio) without standard samples, and the area under the curve (AUC) of plasma concentration per time for evaluation of Safety Testing of Drug Metabolites (MIST) was calculated using the ratio of TB metabolites AUC/total RI AUC. The ratios were as follows: TB 94.5% and HTB 2.5% for the microdose (1.67 microg/kg) and TB 95.6%, HTB 0.96%, CTB 0.065%, M1 0.62%, M2 0.0035%, M3 0.077%, and M4 0.015% for the therapeutic dose (1 mg/kg). These values were less than 10% of the MIST criteria.
机译：液相色谱-放射性同位素质谱（LC-RI-MS）分析用于确定大鼠生物样品（血浆，尿液，胆汁，粪便）中的12种（四种以前未知的）（14种）C-甲苯丁酰胺（TB）代谢物的结构和微粒体）。四种新的代谢产物是ω-羧基TB，羟基TB（HTB）-O-葡萄糖醛酸，TB-邻位或间位谷胱甘肽和甲苯磺酰氨基碳谷胱甘肽。在大鼠血浆中，以治疗剂量（1 mg / kg）和微剂量（1.67 microg / kg）口服（14）C-TB后，总RI和六种代谢物[HTB，羧基TB（CTB），M1：去丁基通过LC-RI-MS对TB，M2：ω-羟基TB，M3：α-羟基TB和M4：ω-1-羟基TB]进行定量。使用没有标准样品的反应因子（MS-RI强度比）计算血浆浓度，并使用该比例计算每次时间的血浆浓度曲线下面积（AUC）以评估药物代谢物的安全性测试（MIST） TB代谢物的AUC /总RI AUC的百分比。比例如下：微剂量（1.67 microg / kg）的TB 94.5％和HTB 2.5％和TB 95.6％，HTB 0.96％，CTB 0.065％，M1 0.62％，M2 0.0035％，M3 0.077％和M4 0.015 ％为治疗剂量（1 mg / kg）。这些值小于MIST标准的10％。

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