氯硝柳胺在小鼠血浆、肌肉及皮肤中的药代动力学研究

Pharmacokinetics study of niclosamide in mouse plasma,muscle and skin

目的 用液相色谱-质谱联用仪（high performance liquid chromatography/mass spectrometry，HPLC/MS）建立氯硝柳胺在小鼠血浆、肌肉和皮肤中的定量分析方法，并用于药代动力学，为氯硝柳胺抗尾蚴侵袭新剂型的研究及药物残留测定方法的建立提供实验数据支持。 方法 采用丙酮提取生物样品中的氯硝柳胺,以对硝基酚为内标，以两者的［M-H］-准分子离子峰m/z 324.9788和138.0186为单离子监测（SIM）产物离子进行定量分析，测定氯硝柳胺在血浆、肌肉和皮肤中的药物含量和药时曲线，计算药峰浓度（Cmax）、生物半衰期（T1/2）及药时曲线下面积（AUC）。 结果 小鼠口服200 mg/kg氯硝柳胺后在血浆、肌肉和皮肤Cmax分别为（2 251.22 ± 31.38）、（250.52± 41.99）和（3 663.01 ± 1 279.52）ng/ml，T1/2分别为（11.07 ± 0.88）、（45.57 ± 0.66）和（14.67 ± 0.31）h，AUC分别为（23 237.± 544）、（8 458 ± 581）和（79 093 ± 1 060）ng/（h·ml）。 结论 氯硝柳胺在小鼠体内的含量测定结果表明，其在皮肤中Cmax及AUC均为最高，说明其易于在皮肤中分布。该性质有利于抗血吸虫尾蚴的侵袭。

Objective To develop an LC/MS method for the quantitative analysis of niclosamide in plas- ma, muscle and skin of mice and apply to its pharmacokinetics, thus to provide experimental data support for the research of anti-cercaria new form of niclosamide and to establish the drug residues analysis approach. Methods Niclosamide in biological samples was extracted by acetone. The quasi-molecular ion peaks m/z 324.9788 and 138.0186 were selected as the fragment of single ion monitoring（SIM） for quantitative determi- nation of niclosamide and p-nitrophenol （internal standard, IS） respectively for analysis of Cmax, T1/2 and AUC in plasma, muscle and skin of mice by HPLC/HRMS. Results The Cmax values of nicloasamide after oral ad- ministration at a dose of 200mg/kg were （2251.22±31.38）, （250.52±41.99） and （3 663.01 ± 1 279.52） ng/ml in plasma, muscle and skin respectively. The T1/2 was （11.07 ± 0.88）, （45.57 ± 0.66） and （14.67 ± 0.31 ） h, respectively, and the AUC was （23 237 ± 544）, （8 458 ± 581 ） and（79 093± 1 060） ng/（h·ml）, respectively. Conclusion The resuhs of Cmax and AUC in the skin indicated that niclosamide is more likely to be distributed in the skin, that is good for anti-invasion of schistosome cercariae.