[人血浆中右啡烷的测定及药代动力学研究]

[Determination of dextrorphan in human plasma and pharmacokinetic study].

作者信息

Liu Dan, Chen Xiao-yan, Zhang Yi-fan, Zhong Da-fang, Gu Qi, Zhang Yong

机构信息

Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China.

出版信息

Yao Xue Xue Bao. 2004 Jun;39(6):449-52.

PMID:15491104

Abstract

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.

摘要

目的

建立一种灵敏且特异的液相色谱-串联质谱法（LC/MS/MS），用于直接测定人血浆中右啡烷，并研究右啡烷的药代动力学。

方法

给18名健康中国男性志愿者单次口服60mg氢溴酸右美沙芬后，测定其活性代谢物右啡烷的血浆浓度。采用液-液萃取法从血浆中提取右啡烷和内标氯苯那敏，然后在Zorbax Extend C18柱上进行分离。流动相由甲醇-水-甲酸（70:30:1）组成，流速为0.5 mL·min⁻¹。使用配备电喷雾电离源的Finnigan TSQ串联质谱仪作为检测器，以正离子模式运行。采用m/z 258至157和m/z 275至230的前体离子与产物离子组合进行选择反应监测（SRM）来定量右啡烷。通过非房室模型统计计算右啡烷的药代动力学参数。

结果

在0.2 - 80μg·L⁻¹浓度范围内获得线性校准曲线。每个血浆样品在3.0分钟内完成色谱分析。在整个浓度范围内，三次验证实验的日内和日间相对标准偏差（RSD）均小于8%。在三个浓度（右啡烷为0.5、6.0和70μg·L⁻¹）下测定的准确度范围为98.8%至100.6%。右啡烷的药代动力学参数如下：达峰时间（Tmax）为（2.1±0.7）小时，峰浓度（Cmax）为（14±8）μg·L⁻¹，半衰期（T1/2）为（3.8±1.8）小时，0至t时间的曲线下面积（AUC0-t）为（60±37）μg·h·L⁻¹。