LC-MS/MS测定人血浆中卡托普利的浓度及其药动学研究

Study on the pharmacokinetic in vivo of captopril in human plasma with LC-MS/MS

目的:建立色谱-串联质谱法测定血浆中卡托普利的浓度,并利用该方法研究了2种国产卡托普利制剂在健康受试者中的药代动力学。方法:用对溴苯乙酰基溴(p-BPB)作为稳定剂及衍生化试剂,以利培酮为内标物,采用 LC-MS/MS 方法测定。以乙腈-0.025%甲酸(60:40)为流动相,色谱柱为 Alltima C_(18)(100 mm×2.1 mm,3.0μm),流速为0.2 mL·min^(-1)。采用大气压化学离子源(APCI),正离子扫描(ESI^+);用于定量分析的离子反应分别为 m/z 414.1→210.6(卡托普利衍生物)和 m/z 411.3→191.1(内标物利培酮)。结果:卡托普利线性范围为1.0～748.0 ng·mL^(-1),定量限为1.0 ng·mL^(-1),日内、日间精密度(RSD)均小于5.8%,平均提取回收率为(103.5±5.8)%。应用此方法研究了18名健康受试者单剂量口服2种卡托普利片50 mg 后的药代动力学特点,2种制剂的 T_(max)(h)分别为0.72±0.19和0.68±0.14,C_(max)(ng·mL^(-1))分别为343.4±132.3和333.6±94.6,T_(1/2)(h)分别为2.07±0.65和2.07±0.69,AUC_(0-t)(ng·h·mL^(-1))分别为442.5±95.6和424.9±78.3。结论:首次报道了用 LC-MS/MS 测定卡托普利衍生物(cap-p-BPB)的浓度。本方法专属、灵敏度高,血浆处理简便,可用于卡托普利制剂的药代动力学及相对生物利用度的研究。

Objective：To establish an LC - MS/MS method for determination of captopril in human plasma and to study the pharmacokinetics for two preparations in healthy volunteers. Methods： Using p - bromophenacyl bromide （p- BPB） as a stabilizer and derivative reagent, the derivates were determined by LC -MS/MS using risperidone as the internal standard. Separation was obtained on Alhima C18 （100 mm × 2. 1 mm,3.0μm）column with the mobile phase of acetonitrile -0. 025% formic acid solution （60： 40） at the flow rate of 0. 2 mL· min^-1. Atmospheric pressure chemical ionization source was applied and operated in positive ion mode. Selected reaction monitoring mode with transitions of m/z 414. 1→210. 6 and m/z 411.3→191.1 was adopted to quantify captopril derivate and internal standard, respectively. Results：The calibration curve of captopril was linear in the range of 1.0 -748.0 ng· mL^-1 and detection limit was 1.0 ng ·mL^-1. The inter - and intra - day precision（RSD） were below 5.8%. The recovery of the method was （ 103.5 ± 5.8） %. To study the pharmacokinetics and the relative bioavailability of two preparations of captopril, tablets were given to 18 healthy volunteers. The pharmacokinetic parameters were reported ： Tmax= （h） were 0.72 ± 0. 19 and 0.68 ± 0. 14, Cm= （ ng ·mL^-1 ） were 343.4 ± 132. 3 and 333.6 ± 94.6, T（1/2） （h） were 2.07 ± 0. 65 and 2. 07 ± 0.69, AUC（0-1） （ ng· h · mL^ -1 ） were 442.5 ± 95.6 and 424. 9 ± 78.3. Conclusion：This method is convenient, sensitive, specific and suitable for pharmacokinetics and relative bioavailability study.