新型抗结核化合物TBI-166在比格犬体内的生物利用度

发布时间：2018-05-11 16:29

本文选题：抗结核药 + TBI-　；参考：《国际药学研究杂志》2015年02期

【摘要】：目的建立比格犬血浆中TBI-166的LC-MS/MS测定方法,研究比格犬口服TBI-166的血浆药代动力学特征和生物利用度。方法比格犬血浆样品中加入TBI-166和内标普萘洛尔后经乙腈沉淀蛋白。HPLC分离采用Symmetry C8(2.1 mm×50 mm,3.5μm)柱,流动相为含0.1%甲酸的乙腈-水,梯度洗脱,流速为0.2 ml/min质谱检测采用电喷雾离子源,正离子选择反应监测(SRM)模式检测m/z 590→478(TBI-166)和m/z 260→183(普萘洛尔,内标)。应用上述LC-MS/MS方法测定比格犬口服TBI-166(3 mg/kg)和静脉注射(0.5 mg/kg)后的血浆药物浓度,用Win Nonlin软件计算药代动力学参数和绝对生物利用度。结果比格犬血浆中TBI-166在2~1000 ng/ml浓度范围内线性关系良好,日内和日间精密度10%、回收率98.6%、无明显基质效应且血浆样品稳定性好。雌雄比格犬口服TBI-166(3mg/kg)后血药浓度分别于(4.4±3.5)和(1.4±0.5)h达峰,血药峰浓度分别为(122.0±34.6)和(65.4±2.3)ng/ml,AUC(0-t)为(2615.1±1524.4)和(897.2±318.6)h·μg/L。雌雄比格犬静注TBI-166(0.5mg/kg)后t1/2z为(112.9±25.3)和(69.6±35.3)h、CL为(0.3±0.1)和(0.2±0.1)L/(h·kg)、AUC(0-t)为(3222.4±1656.2)和(1798.0±729.2)h·μg/L。雌雄比格犬口服TBI-166生物利用度分别为13.5%和8.3%。结论本研究建立了比格犬血浆中TBI-166的LC-MS/MS测定方法,该方法准确、简便、灵敏。比格犬口服TBI-166后体内消除较慢,具有一定性别差异,生物利用度为8.3%~13.5%。
[Abstract]:Objective to establish a LC-MS/MS method for the determination of TBI-166 in Beagle dog plasma and to study the pharmacokinetics and bioavailability of TBI-166. Methods Beagle canine plasma samples were separated by acetonitrile precipitation protein. HPLC. The mobile phase consisted of acetonitrile-water containing 0.1% formic acid, gradient elution, and the flow rate of 0.2 ml/min mass spectrometry was determined by electrospray ion source. The positive ion selective reaction monitoring (SRM) mode was used to detect m / z 590 TBI-166) and m / z 260 / 183 (propranolol, internal standard). The plasma drug concentrations of Beagle dogs after oral administration of TBI-166(3 mg / kg and intravenous injection of 0. 5 mg / kg were determined by the LC-MS/MS method mentioned above. The pharmacokinetic parameters and absolute bioavailability were calculated by Win Nonlin software. Results the linear range of TBI-166 in the plasma of Beagle dogs was 21 000 ng/ml. The precision was 100.The recovery rate was 98.6. There was no obvious matrix effect and the plasma sample was stable. After oral administration of TBI-166 mg / kg, the plasma drug concentrations of male and female Beagle dogs were 4.4 卤3.5) and 1.4 卤0.5 h, respectively, and the peak concentrations were 122.0 卤34.6) and 2615.1 卤1524.4) and 897.2 卤318.6h 渭 g / L, respectively. T 1 / 2z was 112.9 卤25.3g / kg and 69.6 卤35.3h / L respectively, and 0.3222.4 卤1656.2 渭 g / L and 1798.0 卤729.2h 渭 g / L respectively for male and female Beagle dogs after intravenous injection of TBI-166U 0.5 mg 路kg 路kg ~ (-1) and 69.6 卤35.3h / L ~ (-1) and 0.2 卤0.1)L/(h ~ (0-t) for AUC ~ (2 +) and 1798.0 卤729.2h 渭 g 路L ~ (-1) 路L ~ (-1) 路L ~ (-1), respectively. The bioavailability of oral TBI-166 in male and female Beagle was 13. 5% and 8. 3%, respectively. Conclusion the method for the determination of TBI-166 in Beagle dog plasma by LC-MS/MS is accurate, simple and sensitive. After oral administration of TBI-166 in Beagle dogs, the elimination was slower and there was a certain gender difference. The bioavailability was 8.3% and 13.5%.
【作者单位】：中国医学科学院北京协和医学院药物研究所创新药物非临床药物代谢及PK/PD研究北京市重点实验室;
【基金】：十二五新药创制重大专项资助项目(2012ZX09301002-001-007,2012ZX09301002-006,2012ZX09103-101-001)
【分类号】：R965

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