人血浆中O-去甲右美沙芬的测定及药代动力学研究

目的建立直接测定人血浆中O-去甲右美沙芬的方法,并应用于药代动力学研究。方法18名健康受试者单剂量po氢溴酸右美沙芬60 mg后,血浆样品经液-液萃取,通过液相色谱-质谱-质谱联用法测定其活性代谢物O-去甲右美沙芬的浓度,用非室模型计算药代动力学参数。结果O-去甲右美沙芬测定的线性范围为0.2～80 μg·L^-1;其主要药代动力学参数T_max为(2.1±0.7) h,C_max为(14±8) μg·L^-1,T_1/2为(3.8±1.8) h,用梯形法计算,AUC_0-t为(60±37) μg·h·L^-1。结论该法灵敏度高,操作简便,可直接测定活性代谢物,适用于右美沙芬的临床药代动力学研究及制剂的生物等效性评价。

Determination of dextrorphan in human plasma and pharmacokinetic study

AIM: To develop a sensitive and specific LC/MS/MS method for direct determination of dextrorphan in human plasma and to study the pharmacokinetics of dextrorphan. METHODS: After a single oral dose of 60 mg dextromethorphan hydrobromide to 18 healthy Chinese male volunteers, the plasma concentration of dextrorphan, an active metabolite of dextromethorphan, was determined. Dextrorphan and internal standard chlorpheniramine were extracted from plasma using liquid-liquid extraction, then separated on a Zorbax Extend C18 column. The mobile phase consisted of methanol-water-formic acid (70:30:1), at a flow-rate of 0.5 mL x min(-1). A Finnigan TSQ tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor to product ion combinations of m/z 258 to 157 and m/z 275 to 230 was performed to quantify dextrorphan. The pharmacokinetic parameters of dextrorphan were calculated by non-compartment model statistics. RESULTS: The linear calibration curves were obtained in the concentration range of 0.2 - 80 microg x L(-1) Each plasma sample was chromatographed within 3.0 min. The intra- and inter-day relative standard deviation (RSD) across three validation runs over the entire concentration range was less than 8%. Accuracy determined at three concentrations (0.5, 6.0 and 70 microg x L(-1) for dextrorphan) ranged from 98.8% to 100.6%. Pharmacokinetic parameters of dextrorphan was obtained as follows: Tmax was (2.1 +/- 0.7) h, Cmax was (14 +/- 8) microg x L(-1), T1/2 was (3.8 +/- 1.8) h, AUC0-t was (60 +/- 37) microg x h x L(-1). CONCLUSION: Plasma concentration of the active metablite dextrorphan was directly determined. The method is sensitive and convenient, and is proved to be suitable for clinical investigation of dextrorphan pharmacokinetics and bioequivalence evaluation of formulations containing dextromethorphan.