中药透皮制剂在奶牛血和乳中的药动学特征研究
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摘要
由东北农业大学药理教研室自行研制,具有抗菌消炎,活血化淤作用的中药复方透皮制剂,主要用于治疗奶牛临床型乳腺炎。为了研究透皮制剂在奶牛体内的吸收、代谢过程,特进行了本课题的研究。
本试验以反相高效液相色谱法为定量手段,建立了中药复方透皮制剂中的两种有效成分黄芩苷和连翘苷在奶牛乳液和血浆中的检测方法,色谱条件为Kromasil C_(18)色谱柱(4.6×200mm,10μm);流动相:甲醇-0.002%磷酸水溶液(45﹕55);检测波长:280nm。结果表明牛乳中黄芩苷和连翘苷在0.01～5.0μg·mL~(-1)范围内呈良好的线性关系,相关系数r分别为0.9977和0.9958,平均回收率分别为90.39%和88.02%,黄芩苷的平均日内变异系数为1.81%;平均日间变异系数为1.82%;连翘苷的平均日内变异系数为2.69%;平均日间变异系数为3.87%。血浆中黄芩苷和连翘苷在0.01～4.0μg·mL~(-1)范围内呈良好的线性关系,相关系数r分别为0.9955和0.9973,平均回收率分别为89.73%和92.79%,黄芩苷的平均日内变异系数为1.82%;平均日间变异系数为3.28%;连翘苷的平均日内变异系数为2.97%;平均日间变异系数为3.05%。所建立方法的评价指标均在合理范围内,重现性好,精密度高,方便经济,可作为药动学生物样品的检测方法。
以4头患临床型乳腺炎的奶牛为试验动物,在患病乳区局部涂擦中药复方透皮制剂后,分别采集不同时间点的血浆和牛乳样品,采用反相高效液相色谱法测得不同时间点血浆与牛乳中的药物浓度,以MCPKP自动化药动学程序分析数据。试验结果表明,经患病乳区局部涂擦中药复方透皮制剂后,血浆中未能检测到两种有效成分。黄芩苷和连翘苷在牛乳中的药-时数据分析结果表明,两种有效成分在牛乳中的代谢过程属于一级吸收一室开放模型,黄芩苷的理论方程为C=6.2024(e~(0.2271t)-e~(0.3841t)),其主要药动学参数为:T_(max)=4.9392h、C_(max)=2.8399μg·mL~(-1)、t_(1/2k)a=1.803h、AUC=27.32mg·L~(-1)·h~(-1)、lagtime=0.7467h、t_(1/2k)=3.0520h、K=0.2271·h~(-1)、T_(CP)=28.319h;连翘苷的理论方程为C=1.3942(e~(0.3399t)-e~(0.3275t)),其主要药动学参数为:T_(max)=3.6799h、C_(max)=0.4922μg·mL~(-1)、t_(1/2k)a=2.1158h、AUC=4.1015mg·L~(-1)·h~(-1)、lagtime=0.683h、t_(1/2k)=2.0386h、K=0.3399·h~(-1)、T_(CP)=14.525h。
在患病乳区局部涂擦中药复方透皮制剂后,两种有效成分在乳房局部有缓释作用,吸收速率缓慢,吸收程度高,消除较慢,可以充分发挥在乳房局部的治疗作用。选择检测的两种有效成分黄芩苷和连翘苷属于低极性物质,可经扩散作用进入牛乳。中药毒副作用相对较低,目前两种有效成分没有确证的毒理作用,考虑到药物残留问题时,建议以联合应用的抗生素类药物的停药期为准,若没有联合应用抗生素类药物,患乳腺炎奶牛牛乳一旦没有物理、化学性状的改变时,即可饮用。
The traditional Chinese medicine percutaneous preparation had the effect of antisepticizing, antiphlogosis, promoting blood flow and removing blood stasis. It was used to treat the mastitis of cows and was made by the staff of veterinary pharmaco-teaching room in Northeast Agricultural University. The studies on its pharmacokinetics properties were carried out in order to explain its absorbed and metabolic process in cows.
The reversed phase high-performance liquid chromatography (RP-HPLC) method was established in this experiment which was used to detect simultaneously the two effect ingredient (baicalin and forsythin) of the traditional Chinese medicine percutaneous preparation in milk and plasma of cows. Chromatographic condition was that chromatographic column was Kromasil C_(18) (4.6×200mm,10μm); Mobile phase was methanol-0.002% phosphoric acid solution; Detecting wavelength was 280nm.The standard curves of baicalin and forsythin in milk were linear in range of 0.01～5.0μg·mL~(-1), the coefficient of correlation (r) was 0.9977 and 0.9958 respectively.The average recovery of them was 90.39% and 88.02%, respectively. The average coefficient of variation of the bacalin during one day and five days were 1.81% and 1.82%, respectively; The average coefficient of variation of the forsythin during one day and five days were 2.69% and 3.87%, respectively. The standard curves of baicalin and forsythin in plasma were linear in range of 0.01～4.0μg·mL~(-1), the coefficient of correlation were 0.9955 and 0.9973, respectively. The average recovery of them was 89.73% and 92.79%, respectively. The average coefficient of variation of the bacalin during one day and five days were 1.82% and 3.28%, respectively; The average coefficient of variation of the forsythin during one day and five days were 2.97% and 3.05%, respectively. The method can be used for the detection of biological specimen of pharmacokinetics research because of its good reproducibility; high precision; convenience and economics.
The plasma and milk samples were collected at different time point after single percutaneous administration on the breast with disease of the 4 cows. The drug concentration data measuring by the established RP-HPLC were analyzed by MCPKP which was pharmacokinetics auto-analyzing program. The results indicated that baicalin and forsythin had not been detected in plasma after single percutaneous administration on the breast with disease. The results showed that the concentration-time courses of the bacailin and forsythin in the milk fit to a one-compartment open model with the first order absorption after single percutaneous administration on the breast with disease. The theory equation of baicalin in the milk was C=6.2024(e~(0.2271t)-e~(0.3841t)). The main pharmacokinetics parameters of baicalin in the milk were as following, T_(max)=4.9392h, C_(max)=2.8399μg·mL~(-1), t_(1/2k)a=1.803h, AUC=27.32mg·L~(-1)·h~(-1), lagtime=0.7467h, t_(1/2k)=3.0520h, K=0.2271·h~(-1), T_(CP)=28.319h; The theory equation of forsythin in the milk was C=1.3942(e~(0.3399t)-e~(0.3275t)). The main pharmacokinetics parameters of baicalin in the milk were as following, T_(max)=3.6799h, C_(max)=0.4922μg·mL~(-1), t_(1/2k)a=2.1158h, AUC=4.1015mg·L~(-1)·h~(-1), lagtime=0.683h, t_(1/2k)=2.0386h, K=0.3399·h~(-1), T_(CP)=14.525h..
The two effect ingredient had the slow-release action after single percutaneous administration on the breast with disease. They absorbed slowly through the breast but the absorbed degree was high. They eliminated slowly, too.So the traditional Chinese medicine percutaneous preparation brought local action into full play. The baicalin and forsythin got into milk through diffusion because they were the low polarity substance. Because the toxicity of traditional Chinese medicine was relatively low and baicalin and forsythin had not the corroborant toxicity, it was suggested to plan the withdrawal time according to the associated applied antibiotics when the residual was considered.If the antibiotics was not used simultaneouly, the milk can be drink when it had not the physical and chemical changes.
本试验以反相高效液相色谱法为定量手段,建立了中药复方透皮制剂中的两种有效成分黄芩苷和连翘苷在奶牛乳液和血浆中的检测方法,色谱条件为Kromasil C_(18)色谱柱(4.6×200mm,10μm);流动相:甲醇-0.002%磷酸水溶液(45﹕55);检测波长:280nm。结果表明牛乳中黄芩苷和连翘苷在0.01～5.0μg·mL~(-1)范围内呈良好的线性关系,相关系数r分别为0.9977和0.9958,平均回收率分别为90.39%和88.02%,黄芩苷的平均日内变异系数为1.81%;平均日间变异系数为1.82%;连翘苷的平均日内变异系数为2.69%;平均日间变异系数为3.87%。血浆中黄芩苷和连翘苷在0.01～4.0μg·mL~(-1)范围内呈良好的线性关系,相关系数r分别为0.9955和0.9973,平均回收率分别为89.73%和92.79%,黄芩苷的平均日内变异系数为1.82%;平均日间变异系数为3.28%;连翘苷的平均日内变异系数为2.97%;平均日间变异系数为3.05%。所建立方法的评价指标均在合理范围内,重现性好,精密度高,方便经济,可作为药动学生物样品的检测方法。
以4头患临床型乳腺炎的奶牛为试验动物,在患病乳区局部涂擦中药复方透皮制剂后,分别采集不同时间点的血浆和牛乳样品,采用反相高效液相色谱法测得不同时间点血浆与牛乳中的药物浓度,以MCPKP自动化药动学程序分析数据。试验结果表明,经患病乳区局部涂擦中药复方透皮制剂后,血浆中未能检测到两种有效成分。黄芩苷和连翘苷在牛乳中的药-时数据分析结果表明,两种有效成分在牛乳中的代谢过程属于一级吸收一室开放模型,黄芩苷的理论方程为C=6.2024(e~(0.2271t)-e~(0.3841t)),其主要药动学参数为:T_(max)=4.9392h、C_(max)=2.8399μg·mL~(-1)、t_(1/2k)a=1.803h、AUC=27.32mg·L~(-1)·h~(-1)、lagtime=0.7467h、t_(1/2k)=3.0520h、K=0.2271·h~(-1)、T_(CP)=28.319h;连翘苷的理论方程为C=1.3942(e~(0.3399t)-e~(0.3275t)),其主要药动学参数为:T_(max)=3.6799h、C_(max)=0.4922μg·mL~(-1)、t_(1/2k)a=2.1158h、AUC=4.1015mg·L~(-1)·h~(-1)、lagtime=0.683h、t_(1/2k)=2.0386h、K=0.3399·h~(-1)、T_(CP)=14.525h。
在患病乳区局部涂擦中药复方透皮制剂后,两种有效成分在乳房局部有缓释作用,吸收速率缓慢,吸收程度高,消除较慢,可以充分发挥在乳房局部的治疗作用。选择检测的两种有效成分黄芩苷和连翘苷属于低极性物质,可经扩散作用进入牛乳。中药毒副作用相对较低,目前两种有效成分没有确证的毒理作用,考虑到药物残留问题时,建议以联合应用的抗生素类药物的停药期为准,若没有联合应用抗生素类药物,患乳腺炎奶牛牛乳一旦没有物理、化学性状的改变时,即可饮用。
The traditional Chinese medicine percutaneous preparation had the effect of antisepticizing, antiphlogosis, promoting blood flow and removing blood stasis. It was used to treat the mastitis of cows and was made by the staff of veterinary pharmaco-teaching room in Northeast Agricultural University. The studies on its pharmacokinetics properties were carried out in order to explain its absorbed and metabolic process in cows.
The reversed phase high-performance liquid chromatography (RP-HPLC) method was established in this experiment which was used to detect simultaneously the two effect ingredient (baicalin and forsythin) of the traditional Chinese medicine percutaneous preparation in milk and plasma of cows. Chromatographic condition was that chromatographic column was Kromasil C_(18) (4.6×200mm,10μm); Mobile phase was methanol-0.002% phosphoric acid solution; Detecting wavelength was 280nm.The standard curves of baicalin and forsythin in milk were linear in range of 0.01～5.0μg·mL~(-1), the coefficient of correlation (r) was 0.9977 and 0.9958 respectively.The average recovery of them was 90.39% and 88.02%, respectively. The average coefficient of variation of the bacalin during one day and five days were 1.81% and 1.82%, respectively; The average coefficient of variation of the forsythin during one day and five days were 2.69% and 3.87%, respectively. The standard curves of baicalin and forsythin in plasma were linear in range of 0.01～4.0μg·mL~(-1), the coefficient of correlation were 0.9955 and 0.9973, respectively. The average recovery of them was 89.73% and 92.79%, respectively. The average coefficient of variation of the bacalin during one day and five days were 1.82% and 3.28%, respectively; The average coefficient of variation of the forsythin during one day and five days were 2.97% and 3.05%, respectively. The method can be used for the detection of biological specimen of pharmacokinetics research because of its good reproducibility; high precision; convenience and economics.
The plasma and milk samples were collected at different time point after single percutaneous administration on the breast with disease of the 4 cows. The drug concentration data measuring by the established RP-HPLC were analyzed by MCPKP which was pharmacokinetics auto-analyzing program. The results indicated that baicalin and forsythin had not been detected in plasma after single percutaneous administration on the breast with disease. The results showed that the concentration-time courses of the bacailin and forsythin in the milk fit to a one-compartment open model with the first order absorption after single percutaneous administration on the breast with disease. The theory equation of baicalin in the milk was C=6.2024(e~(0.2271t)-e~(0.3841t)). The main pharmacokinetics parameters of baicalin in the milk were as following, T_(max)=4.9392h, C_(max)=2.8399μg·mL~(-1), t_(1/2k)a=1.803h, AUC=27.32mg·L~(-1)·h~(-1), lagtime=0.7467h, t_(1/2k)=3.0520h, K=0.2271·h~(-1), T_(CP)=28.319h; The theory equation of forsythin in the milk was C=1.3942(e~(0.3399t)-e~(0.3275t)). The main pharmacokinetics parameters of baicalin in the milk were as following, T_(max)=3.6799h, C_(max)=0.4922μg·mL~(-1), t_(1/2k)a=2.1158h, AUC=4.1015mg·L~(-1)·h~(-1), lagtime=0.683h, t_(1/2k)=2.0386h, K=0.3399·h~(-1), T_(CP)=14.525h..
The two effect ingredient had the slow-release action after single percutaneous administration on the breast with disease. They absorbed slowly through the breast but the absorbed degree was high. They eliminated slowly, too.So the traditional Chinese medicine percutaneous preparation brought local action into full play. The baicalin and forsythin got into milk through diffusion because they were the low polarity substance. Because the toxicity of traditional Chinese medicine was relatively low and baicalin and forsythin had not the corroborant toxicity, it was suggested to plan the withdrawal time according to the associated applied antibiotics when the residual was considered.If the antibiotics was not used simultaneouly, the milk can be drink when it had not the physical and chemical changes.
引文
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