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目的建立检测大鼠血浆中抗人类免疫缺陷病毒(human immunodeficiency virus,HIV)候选化合物DAAN-5508的LCMS/MS方法,并将其应用于大鼠体内药动学研究。方法血浆样品用甲醇沉淀蛋白处理;色谱分离用含0.1%甲酸的甲醇和水为流动相梯度洗脱,流速为0.3 mL·min-1。定量分析在Triple Quad LC-MS/MS上采用电喷雾离子化电离源(ESI)、正离子多重反应离子监测(MRM)的方式进行。将建立的方法应用于大鼠静注和口服DAAN-5508的药动学和生物利用度研究。结果 DAAN-5508在0.2~2 500 ng·mL-1内呈良好的线性关系(r2=0.999 8),最低定量限为0.2 ng·mL-1,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-1)和口服(15 mg·kg-1)DAAN-5508后,静注和口服的消除半衰期分别为2.6和4.6 h。大鼠口服后DAAN-5508的吸收较快,血浆浓度在1 h左右达到(188.0±62.33)ng·mL-1的峰值,口服生物利用度为12%。结论本实验建立了特异、灵敏、简便快捷的定量检测血浆DAAN-5508的LC-MS/MS方法,成功应用于DAAN-5508的大鼠药动学和生物利用度研究。
Objective To establish a LCMS / MS method for the detection of DAAN-5508, a candidate compound of human immunodeficiency virus (HIV) in rat plasma and to apply it in rat pharmacokinetic studies. Methods The plasma samples were treated with methanol precipitated protein. The chromatographic separation was performed on a gradient elution of methanol and water containing 0.1% formic acid at a flow rate of 0.3 mL · min-1. Quantitative analysis was performed on Triple Quad LC-MS / MS using electrospray ionization ionization source (ESI), positive ion multiple reaction ion monitoring (MRM). The established method was applied to the pharmacokinetics and bioavailability of DAAN-5508 in rats by intravenous and oral administration. Results The linear range of DAAN-5508 was 0.2-2 500 ng · mL-1 (r2 = 0.999 8). The lowest limit of quantification was 0.2 ng · mL-1. The recovery rate was> 80% Precision and accuracy meet the testing requirements of biological samples. After intravenous (5 mg · kg-1) and oral (15 mg · kg-1) DAAN-5508, the elimination half-lives of rats and mice were 2.6 and 4.6 h, respectively. After oral administration, DAAN-5508 absorbed fast, and the plasma concentration reached the peak of (188.0 ± 62.33) ng · mL-1 after 1 h. The oral bioavailability was 12%. Conclusion This study established a specific, sensitive, simple and quick LC-MS / MS method for the quantitative detection of plasma DAAN-5508. The pharmacokinetics and bioavailability of DAAN-5508 were studied successfully.