机构地区:[1]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,北京100050
出 处:《国际药学研究杂志》2015年第2期194-198,205,共6页Journal of International Pharmaceutical Research
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)
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%。Objective To develop a LC-MS/MS method for the quantification of TBI-166,a novel antituberculotic,in beagle dog plasma,and apply it to the pharmacokinetic and bioavailability study. Methods The preparation of plasma sample was a simple deproteinization by the addition of acetonitrile followed by centrifugation. The separation was performed on a Symmetry C8column(2.1 mm × 50 mm,3.5μm)with mobile phase of acetonitrile/water containing 0.1% formic acid(V/V)using a gradient elution mode at a flow rate of 0.2 ml/min. The detection was performed in positive selected reaction monitoring(SRM) mode with an electrospray ionization source. The analytes were quantified at m/z 590→478 for TBI-166 and m/z 260→183 for propranolol(internal standard,IS). Results Linear detection responses were obtained for TBI-166 in dog plasma ranging from 2 to 1000 ng/ml. The intra-and inter-day precisions(RSD%) were no more than 10%. The average recovery was greater than 98.6%,and there was good stability and no obvious matrix effect for the quantification. The method was successfully applied in the pharmacokinetic study of TBI-166 in beagle dogs. The AUC(0-t),Cmaxand Tmaxof TBI-166 in male and female dogs were(897.2±318.6)and(2615.1±1524.4)h·μg/L,(65.4±2.3)and(122.0±34.6)ng/ml and(1.4±0.5)and(4.4±3.5) h after oral administration at 3 mg/kg. The t1/2z,AUC(0-t),and CL of TBI-166 in male and female dogs were(69.6±35.3)and(112.9±25.3)h,(1798.0±729.2)and(3222.4±1656.2)h·μg/L,(0.2±0.1)and(0.3 ±0.1) L/(h·kg) after intravenous administration at 0.5 mg/kg. Conclusion An accurate,simple and sensitive LC-MS/MS method for the determination of TBI-166 in beagle dog plasma was developed and validated. This method was applied to the pharmacokinetic study of TBI-166 in beagle dogs. There was a gender difference on the pharmacokinetic profiles of TBI-166 in dogs.TBI-166 was eliminated slowly and the bioavailability of TBI-166 was 8.3-13.5% in male and female
关 键 词:抗结核药 TBI-166 液相色谱-质谱联用法 药代动力学 生物利用度
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