LC-MS/MS法测定甲氯噻嗪血浓度及药动学研究

目的为了获得国产甲氯噻嗪在中国人体内的代谢情况,以便指导临床合理用药,对国产的甲氯噻嗪片在健康中国男性受试者中空腹单剂量口服不同剂量时的药动学特点进行评价。方法采用LC-MS/MS法测定血浆中甲氯噻嗪的浓度并用非房室模型计算药动学参数。结果入选的10名受试者单剂量口服3种不同剂量(2.5、5.0和10mg)的甲氯噻嗪后的AUC0→t分别为:(128.40±20.88)、(257.68±37.10)和(517.27±119.17)μg·h·L~(~(-1));AUC0→∞分别为:(150.47±24.78)、(299.52±45.56)和(602.57±129.67)μg·h·L~(-1);cmax分别为(8.43±2.21)、(16.60±2.53)和(32.08±8.44)μg·L~(-1);tmax分别为(2.60±0.70)、(2.30±0.95)和(3.25±1.27)h;T1/2分别为(17.63±2.61)、(17.37±2.62)和(17.87±2.49)h;Ka分别为(1.195±0.720)、(1.352±0.626)和(1.221±1.152)h~(-1);Ke分别为(0.0344±0.105)、(0.0391±0.0103)和(0.0362±0.0081)h~(-1);Vd分别为(236.36±69.20)、(221.79±87.94)和(299.30±204.72)L;CL分别为(0.0174±0.0039)、(0.0178±0.0035)和(0.0179±0.0036)L·h~(-1)。结论AUC0→t(r=1)和cmax(r=0.9998)在2.5~10mg范围内呈良好的线性关系。tmax和T1/2经ANOVA(SPSS10.0)统计学处理3种不同剂量间差别无统计学意义。剂量校正后AUC0→t和cmax的几何均数分别是:50.69、51.04、50.39μg·h·L~(-1)和3.26、3.28、3.06μg·L~(-1),其值基本相近。

Study of pharmacokinetics and LC-MS/MS method of blood concentration of methyclothiazide

AIM To evaluate the safety and pharmacokinetic parameters of a domestic methyclothiazide tablet in Chinese healthy male volunteers after administered three different oral dosage. METHODS Ten healthy Chinese volunteers were given a different single oral dosage domestic methyclothiazide tablet. The concentration of methyclothiazide in blood plasma was measured by an validated LC-MS/MS method and were assessed with non-compartment model to obtain the pharmacokinetic parameters. RESULTS The pharmacokinetic parameters of methyclothiazide tablet for orally administered different dosage (2.5,5.0,10mg) were as follows: AUC0→t: (128.40 ± 20.88), (257.68 ± 37.10) and (517.27 ±119.17)μg·h· L-1; AUC0→∞: (150.47 ± 24.78), (299.52 ± 45.56) and (602.57 ± 129.67)μg· h·L-1; cmax:(8.43 ± 2.21) ,(16.60±2.53) and (32.08 ± 8.44)μg·L-1; tmax:(2.60 ± 0.70) ,(2.30 ± 0.95) and (3.25 ± 1.27)h;T1/2:(17.63 ± 2.61), (17.37 ± 2.62) and (17.87 ± 2.49)h; Ka: (1. 195 ± 0.720), (1.352 ± 0.626) and(1.221± 1.152) h-1;Ke: (0.0344 ± 0.1050),(0.0391 ± 0.0103) and (0.0362 ±0.0081) h-1; Vd: (236.36 ±69.20), (221.79 ± 87.94) and (299.30 ± 204.72) L;CL: (0.0174 ± 0.0039), (0.0178 ± 0.0035) and (0.0179 ±0.0036) L· h-1. CONCLUSION The results show that there was a good linear in AUC0→t (r = 1 ) and cmax (r =0.999 8) in dosage range of 2.5-10 mg. There is no significant difference in tmax and T1/2 between three different dosage groups (SPSS 10.0). The geometric mean of AUC0→t and cmax after dose is rectified are 50.69,51.04,50.39 μg·h·L-1and 3.26,3.28,3.06 μg· L- 1, respectively. No any adverse drug reactions are found during the whole study.