液质联用法测定左旋氨氯地平的血药浓度及其片剂的相对生物利用度研究

Determination of Levamlodipine in Human Plasma by LC-MS/MS and Its Application to Relative Bioavailability

目的建立液相色谱-串联质谱法测定人血浆中左旋氨氯地平的浓度,研究2种苯磺酸左旋氨氯地平片的人体药动学及相对生物利用度。方法血浆样品中加入内标硝苯地平,经乙醚-二氯甲烷(3:1)提取,采用液相色谱-串联质谱法。用建立的方法测定20例健康男性受试者单剂量口服苯磺酸左旋氨氯地平受试制剂或参比制剂后的血药浓度,求得药动学参数,并对2种制剂的生物等效性进行评价。结果在0.1～20.0μg·L^(-1)内呈良好的线性关系,方法回收率为99.9%～101.7%,日内、日间RSD均小于15%。单次po 5 mg苯磺酸左旋氨氯地平受试制剂或参比制剂后的t_(max)分别为(7.80±2.67)和(7.00±2.00)h;ρ_(max)分别为(3.01±1.00)和(3.17±0.93)μg·L^(-1);t_(1/2)分别为(42.3±17.4)和(39.2±15.0)h;AUC_(0-t)分别为(111.2±29.2)和(116.8±31.1)μg·h·L^(-1);AUC_(0-∞)分别为(131.3±35.5)和(136.5±32.5)μg·h·L^(-1)。受试制剂对参比制剂的相对生物利用度为(95.9±13.5) %。结论该方法灵敏,无杂质干扰。测得的受试制剂与参比制剂的主要药动学参数之间无明显差异,表明2种制剂在人体内生物等效。

OBJECTIVE To determine levamlodipine in human plasma by LC-MS/MS method, and to investigate its pharmacokinetics and relative bioavailability. METHODS Levamlodipine concentrations in plasma extracted with aether： dichlormethane （3 ： 1） were determinated by LC-MS/MS. The test and reference formulations were given to 20 healthy male volunteers. Pharmacokinetics and hioequivalence were evaluated. RESULTS The calibration curve was linear within the range of 0.1-20.0 μg·L^-1. The method recovery was 99.9%-101.7%. RSDs of intra-day and inter-day were less than 15%. After a single oral dose of 5 mg levamlodipine besilate test or reference tablets, the main pharmacokinetic parameters were as follows： tmax （7.80±2.67） and （7.00±2.00） h, ρmax（3.01±1.00） and （3.17±0.93） μg·L^-1, t1/2 （42.3±17.4） and （39.2±15.0） h, AUC0-t （111.2±29.2） and （116.8 ± 31.1 ） μg·h·L^-1, AUC0-∞ （131.3 ± 35.5） and （136.5 ± 32.5） μg·h·L^-1, respectively. Relative bioavailability was （95.9 ±13.5） %. CONCLUSION The method is sensitive with no endogenous interference. No significant difference exists among the main pharmacokinetic parameters for the test and reference tablets. The two formulations are bioequivalence.