抗HIV候选化合物DAPA-7035的大鼠药代动力学研究  

Pharmacokinetics study of anti-HIV candidate DAPA-7035 in rat

作　　者：王瑞[1] 原梅[1] 王生彪[1] 谢剑炜[1] 李桦[1] 谢蓝[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《国际药学研究杂志》2012年第3期251-255,共5页Journal of International Pharmaceutical Research

基　　金：国家自然科学基金重点项目(30930106);国家"重大新药创制"科技重大专项(2008ZXJ09006-001)

摘　　要：目的建立检测大鼠血浆中抗HIV候选化合物DAPA-7035的LC-MS/MS方法,并将其应用于大鼠体内药代动力学研究。方法血浆样品用甲醇沉淀蛋白处理;色谱分离在资生堂CAPCELL PAK C18柱(MGⅢ,150 mm×2.0 mm,5μm)上用含0.1%甲酸的甲醇和水为流动相梯度洗脱,流速为0.3 ml/min。定量分析在Agilent 6430 Triple Quad LC-MS/MS上采用电喷雾离子化电离源(ESI)、正离子多反应监测的方式进行,检测离子对分别为m/z 382.2→197(DAPA-7035)和m/z 390.1→208(内标)。将建立的方法应用于大鼠静注和口服DAPA-7035的药代动力学研究。结果 DAPA-7035在0.1～2500 ng/ml的浓度范围内呈良好的线性关系(r2=0.9985),最低定量限为0.1 ng/ml,方法的回收率>80%,日内和日间精密度和准确度符合生物样品的检测要求。大鼠静注(5 mg/kg)和口服(15 mg/kg)DAPA-7035后,静注和口服的消除半衰期分别为3.77 h和5.34 h。大鼠口服后DAPA-7035的吸收较快,血浆浓度在1.6 h左右达到(298.4±42.9)ng/ml的峰值,口服生物利用度为15.3%。结论本研究首次建立了特异、灵敏、简便快捷的定量检测血浆DAPA-7035的LC-MS/MS方法,成功应用于DAPA-7035的大鼠药代动力学和生物利用度研究。Objective To develop and validate a LC-MS/MS method for quantitative analysis of the new anti-HIV candidate DAPA-7035 in rat plasma, and to study its phannacokinetics and bioavailability in rats. Methods The plasma samples were treated with methanol for precipitating proteins. The chromatographic separation of DAPA-7035 and the internal standard were performed on a CAPCELL PAK Cls column （MGⅢ,150 mm×2.0 mm,5μm,i. d, Shiseido, Japan） with a gradient elution using 0. 1% formic acid solution and methanol containing 0. 1% formic acid. The flow rate was 0. 3 ml/min. The MS detection was conducted using an Agilent 6430 LC-MS/MS in positive ion electrospray and multiple reactions monitoring （MRM） mode. The transitions monitored were m/z 382. 2→197 and 390. 1→208 for DAPA-7035 and internal standard, respectively. Results A good linearity was obtained over the concentration range of 0. 1-2500 ng/ml for DAPA-7035 （ r2 = 0. 9985 ）, with the lower limit of quantification at 0. 1 ng/ml. The recovery of DAPA-7035 was greater than 80%. The precison and the accuracy met the requirements to bioanalysis. The method was applied for pharmacokinetics study of DAPA-7035 in rat. After a single iv（5 mg/kg）or oral dose （15 mg/kg）of DAPA-7035 to rats, the half-lives were 3.77 h and 5.34 h for intravenous and oral administration, respectively. The absorption of DAPA-7035 was rapid after oral dose. The peak level （298.4 ± 42. 9） ng/ml was reached at 1.6 h. The oral bioavailability was 15.3%. Conclusion The results of the study showed that the LC-MS/MS method is selective, sensitive, rapid and simple. It is suitable for the in vivo pharmaco- kinetics study of DAPA-7035 in rat.

关 键 词：非核苷类逆转录酶抑制剂 二芳烃取代吡啶胺类化合物 液相色谱-串联质谱法 药代动力学 生物利用度 

分 类 号：R96[医药卫生—药理学]