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比格犬经口给予雄黄和牛黄解毒片后血浆中砷化学态的研究

Arsenic speciation by HPLC-HG-AFS after oral administration of realgar and Niuhuang Jiedu Pian in Beagle dogs

  • 摘要: 建立了比格犬血浆中4种砷化学态三价无机砷As(Ⅲ)、五价无机砷As(Ⅴ)、一甲基砷(MMA)和二甲基砷(DMA)\的液相色谱 氢化物发生 原子荧光(HPLC-HG-AFS)测定法,并用于比格犬灌胃给予牛黄解毒片和雄黄后血浆中砷化学态的比较研究。血浆样品经甲醇沉淀蛋白、上清液减压挥干浓缩、残渣以流动相复溶离心后,取上清液,采用Hamilton PRP-X 100阴离子交换色谱柱(250 mm×4.1 mm,10 μm),以15 mmol/L磷酸二氢钾(氢氧化钾溶液调至pH 5.9)为流动相,进行HPLC-HG-AFS分析,4种砷化学态在15 min内得到良好分离。6只比格犬随机双交叉单次经口给予雄黄(以砷元素计,相当于11 mg/kg)和牛黄解毒片(以砷元素计,相当于28 mg/kg),测得血浆中的主要砷化学态均为DMA,并有少量As(Ⅴ),未测得As(Ⅲ)或MMA。比格犬单次给药雄黄和牛黄解毒片后DMA的主要药代动力学参数:cmax分别为(14.7±4.2)和(57.0±32.0)ng/mL,tmax分别为(2.4±0.5)和(2.5±0.5)h,AUC0-36 h分别为(151±13)和(636±418)ng·h/mL,t1/2分别为(16.2±7.9)和(9.4±2.2)h。与雄黄相比,给药牛黄解毒片后DMA的cmax和AUC明显增加,而t 1/2显著减小,表明经牛黄解毒片配伍后,DMA的转化增加,而消除加快,说明牛黄解毒片复方配伍对砷的药代动力学行为有影响。

     

    Abstract: A high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) method was developed for the simultaneous determination of arsenite As(III),arsenate As(V),monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in dog plasma.The plasma samples were treated with methanol and the supernatant was evaporated to dryness under reduced pressureThe residue was reconstituted with mobile phase and the supernatant obtained after centrifugation was injected for the HPLC-HG-AFS analysis.The separation of the arsenicals was performed on a Hamilton PRP-X 100 anion-exchange column (250 mm×4.1 mm,10 μm) with isocratic elution by 15 mmol/L monopotassium phosphate solution (adjusted to pH 5.9 with KOH solution).The separation of the four arsenic species was achieved within 15 min.The method was applied to the arsenic speciation study in beagle dogs after single oral administration of realgar (equivalent to 11 mg As/kg) alone or Niuhuang Jiedu Pian (equivalent to 28 mg As/kg),respectively.DMA was found to be the predominant species in the dog plasma after dosing,with As(V) appeared as the quickly eliminating one.No traces of MMA or As(III) were detected at any sampling time.The main pharmacokinetic parameters found for DMA after oral administration of realgar and Niuhuang Jiedu Pian were as follows:cmax (14.7±4.2) and (57.0±32.0) ng/mL,tmax (2.4±0.5) and (2.5±0.5) h,AUC0-36 h (151±13) and (636±418) ng ·h/mL,t1/2(16.2±7.9) and (9.4±2.2) h,respectively.The influence of compounding in Niuhuang Jiedu Pian on the pharmacokinetics of arsenics was shown with significantly increased transformation of DMA and its faster elimination rate,suggesting the pharmacokinetic behavior of the arsenic was influenced by the compatibility effects of other ingredients in the compound preparation of Niuhuang Jiedu Pian.

     

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