猪肝CYP450 3A4和2D6活性及几种兽药对其影响的初步研究
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摘要
CYP450 3A4和2D6是肝细胞色素P450药物代谢酶家族中两钟最重要的酶,分别参与了整个酶系代谢药物中60%和30%的药物代谢。通过对CYP3A4和2D6酶的研究可以进一步明确药物相互作用的机制,预防和减轻药物间的相互作用,最大限度地提高药物有效性和安全性,也可用于新药的筛选与安全性评价。同时通过测定CYP3A4和2D6酶活性可以指导临床合理地联合用药,预测药物潜在毒性和可能发生的不良反应。目前有关猪的CYP450酶系的研究很少,而关于常用兽药对于猪CYP 3A4和2D6的研究在国内外均处于空白。本研究建立了探针药物法检测猪肝CYP 3A4和2D6活性的方法,同时研究了多西环素、泰乐菌素和头孢喹肟三种药物对这两种酶的活性影响。
1用探针药物咪达唑仑研究猪肝CYP450 3A4活性
以高压液相色谱(HPLC)法为定量手段,通过研究CYP3A4探针药物咪达唑仑在健康苏钟猪体内的药动学特征,建立在猪肝CYP450 3A4体内活性的研究方法。50-60日龄苏钟猪6头,肌肉注射咪达唑仑后,前腔静脉采血后,处理好血浆进样,用高压液相色谱法检测,经3p97分析。结果:日内、日间误差分别小于3.74%和4.32%,方法的回收率高于90.60±2.53%,在0.05-25μg/ml血浆浓度范围内呈线性关系(R2=0.9993),最低检测浓度为0.05μg/ml。血浆药物浓度-时间数据符合一级吸收二室开放模型,咪达唑仑主要动力学参数分别为:t1/2α为0.23±0.07 h,t1/2β为0.30±0.04h,CL(s)为2.10±0.55 L/h,AUC为0.97±0.17μg·h/mL。这些参数同文献报道的结果一致,说明在健康猪体内的CYP3A4酶活性较好。
2用探针药物氢溴酸右美沙芬研究CYP450 2D6活性
以高压液相色谱(HPLC)法为定量手段研究了CYP2D6探针药物氢溴酸右美沙芬在健康苏钟猪体内的药动学特征,建立猪肝CYP450 2D6活性的体内研究方法。50-60日龄猪6头。灌服氢溴酸右美沙芬后,前腔静脉采血后,处理好血浆进样,用高压液相色谱法检测,经3p97分析后发现:血浆药物浓度-时间数据符合一级吸收一室开放模型,灌服氢溴酸右美沙芬主要动力学参数分别为:t1/2α为0.86±0.24 h,t1/2β为2.58±0.22h,CL(s)为0.22±0.03 L/h,AUC为4.52±0.41μg·h/mL。排除钟属差异,结果和文献报道的基本一致,反应了健康猪体内的CYP 450 2D6活性较好。
3多西环素、泰乐菌素和头孢喹肟对猪肝CYP450 3A4和2D6活性的影响
采用体内探针药物(咪达唑仑、氢溴酸右美沙芬)代谢的方法,研究多西环素、泰乐菌素和头孢喹肟对猪肝细胞CYP450 3A4和2D6亚型有无诱导或者抑制作用,为兽医临床用药提供参考。将24头猪随机等分为对照组(生理盐水),多西环素诱导组(5mg/kg·bw),泰乐菌素诱导组(10mg/kg·bw)和头孢喹肟诱导组(2mg/kg·bw)连续用药7天后,用高效液相色谱法分别测定咪达唑仑和氢溴酸右美沙芬在四组猪体内代谢过程中不同时间点的血药浓度,并计算药动学参数。结论:其中,在对CYP 3A4亚型的研究中发现,同对照组相比,T1/2β(消除半衰期)多西环素和泰乐菌素诱导组均显著升高(P＜0.01),头孢喹肟组显著下降(P＜0.01);多西环素组的CL(s)(总体清除率)显著减小(P＜0.01),头孢喹肟的CL(s)(总体清除率)显著增大(P＜0.01);多西环素组的AUC(药-时曲线下面积)显著增大(P＜0.01),头孢喹肟组的AUC(药-时曲线下面积)显著减小(P＜0.01);间接证明了多西环素对猪肝CYP3A4有较强的抑制作用,而头孢喹肟对其有较强的诱导作用。在对CYP 2D6亚型的研究中发现,同对照组相比,T1/2β(消除半衰期)三个实验组均显著升高(P＜0.01);头孢喹肟组的CL(s)(总体清除率)显著减小(P＜0.01);头孢喹肟组的AUC(药-时曲线下面积)显著增大;间接证明了头孢喹肟对猪肝CYP450 2D6有较强的抑制作用,而多西环素和泰乐菌素对它的轻微抑制。
1 The activity studies of Midazolam CYP450 3A4 probe in pigs
A rapid accurate and sensitive high performance chromatographic method was developed for the determination of activity of hepatic CYP450 3A4 in pigs with Midazolam probe.The calibration curves were linear over a wide range of concentrations (0.05～25μg/ml),and the detection limit of Midazolam was 0.05μg/ml.The precisions (RSD%,n=5) of within day and day to day were less than 6.5%and 15%,respectively.The pharmacokinetic characteristics of Midazolam in pigs after after oral administration 2 mg/kg were best described by an open two-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows,respectively:t1/2α:0.23±0.07 h,t1/2β:0.30±0.04 h,CL(s):2.10±0.55 L/h,AUC:0.97±0.17μg·h/mL.It is close with results in literature and showed that hepatic CYP 3A4 is acticve in pigs
2 The activity studies of dextromethorphan P450 2D6 probe in pig
The activity of hepatic CYP450 2D6 were investigated with dextromethorphan probe in pig by HPLC method.The pharmacokinetic characteristics of dextromethorphan in pig after oral administration 1 mg/kg were best described by an open one-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows, respectively:t1/2α0.86±0.24 h,t1/2β2.58±0.22 h,CL(s),4.52±0.41μg·h/mL.it showed that the activity of hepatic CYP450 2D6 is active in health pigs.
3 Study the effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigs
The effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigs was estimated with Midazolam and Dextromethorphan as probe. 24 pigs were randomly divided into control group(administered with physiological saline), Doxycycline-treated group(5mg/kg·bw,i.p.×7 d),Tiamulin-treated group(5mg/kg·bw, i.p.×7 d)and Cefquinome-treated group(1mg/kg·bw,i.p.×7 d).The plasma concentrations of Midazolam and Dextromethorphan were determined by HPLC.The pharmacokinetic parameters were estimated.The results:In the reach about CYP 3A4,Compared with the saline-treated control group,the T1/2βof Midazolam for Doxycycline and Tiamulin groups is were sharply prolonged(p＜0.01),and the Cefquinome group is significantly shorted(p＜0.01).The CL(s) for Doxycycline group is significantly decreased(p＜0.01),the Cefquinnime group is sharply increased.The AUC for Doxycyline group is sharply increased(p＜0.01),the Cefquinnime group is significantly deereased(p＜0.01).It is showed that activity of CYP 450 3A4 could be markedly inhibited by Doxycycline,and Cefquinome could be a strong inducer.In the reach about CYP 2D6,Compared with the control group,the T1/2βof Dextromethorphan for all the groups were sharply prolonged(p＜0.01).The CL(s) for Cefquinnime group is significantly decreased(p＜0.01). The AUC for Cefquinnime group is sharply inereased(p＜0.01).It is indicated that activity of CYP 450 2D6 could be strongly inhibited by Cefquinome.
1用探针药物咪达唑仑研究猪肝CYP450 3A4活性
以高压液相色谱(HPLC)法为定量手段,通过研究CYP3A4探针药物咪达唑仑在健康苏钟猪体内的药动学特征,建立在猪肝CYP450 3A4体内活性的研究方法。50-60日龄苏钟猪6头,肌肉注射咪达唑仑后,前腔静脉采血后,处理好血浆进样,用高压液相色谱法检测,经3p97分析。结果:日内、日间误差分别小于3.74%和4.32%,方法的回收率高于90.60±2.53%,在0.05-25μg/ml血浆浓度范围内呈线性关系(R2=0.9993),最低检测浓度为0.05μg/ml。血浆药物浓度-时间数据符合一级吸收二室开放模型,咪达唑仑主要动力学参数分别为:t1/2α为0.23±0.07 h,t1/2β为0.30±0.04h,CL(s)为2.10±0.55 L/h,AUC为0.97±0.17μg·h/mL。这些参数同文献报道的结果一致,说明在健康猪体内的CYP3A4酶活性较好。
2用探针药物氢溴酸右美沙芬研究CYP450 2D6活性
以高压液相色谱(HPLC)法为定量手段研究了CYP2D6探针药物氢溴酸右美沙芬在健康苏钟猪体内的药动学特征,建立猪肝CYP450 2D6活性的体内研究方法。50-60日龄猪6头。灌服氢溴酸右美沙芬后,前腔静脉采血后,处理好血浆进样,用高压液相色谱法检测,经3p97分析后发现:血浆药物浓度-时间数据符合一级吸收一室开放模型,灌服氢溴酸右美沙芬主要动力学参数分别为:t1/2α为0.86±0.24 h,t1/2β为2.58±0.22h,CL(s)为0.22±0.03 L/h,AUC为4.52±0.41μg·h/mL。排除钟属差异,结果和文献报道的基本一致,反应了健康猪体内的CYP 450 2D6活性较好。
3多西环素、泰乐菌素和头孢喹肟对猪肝CYP450 3A4和2D6活性的影响
采用体内探针药物(咪达唑仑、氢溴酸右美沙芬)代谢的方法,研究多西环素、泰乐菌素和头孢喹肟对猪肝细胞CYP450 3A4和2D6亚型有无诱导或者抑制作用,为兽医临床用药提供参考。将24头猪随机等分为对照组(生理盐水),多西环素诱导组(5mg/kg·bw),泰乐菌素诱导组(10mg/kg·bw)和头孢喹肟诱导组(2mg/kg·bw)连续用药7天后,用高效液相色谱法分别测定咪达唑仑和氢溴酸右美沙芬在四组猪体内代谢过程中不同时间点的血药浓度,并计算药动学参数。结论:其中,在对CYP 3A4亚型的研究中发现,同对照组相比,T1/2β(消除半衰期)多西环素和泰乐菌素诱导组均显著升高(P＜0.01),头孢喹肟组显著下降(P＜0.01);多西环素组的CL(s)(总体清除率)显著减小(P＜0.01),头孢喹肟的CL(s)(总体清除率)显著增大(P＜0.01);多西环素组的AUC(药-时曲线下面积)显著增大(P＜0.01),头孢喹肟组的AUC(药-时曲线下面积)显著减小(P＜0.01);间接证明了多西环素对猪肝CYP3A4有较强的抑制作用,而头孢喹肟对其有较强的诱导作用。在对CYP 2D6亚型的研究中发现,同对照组相比,T1/2β(消除半衰期)三个实验组均显著升高(P＜0.01);头孢喹肟组的CL(s)(总体清除率)显著减小(P＜0.01);头孢喹肟组的AUC(药-时曲线下面积)显著增大;间接证明了头孢喹肟对猪肝CYP450 2D6有较强的抑制作用,而多西环素和泰乐菌素对它的轻微抑制。
1 The activity studies of Midazolam CYP450 3A4 probe in pigs
A rapid accurate and sensitive high performance chromatographic method was developed for the determination of activity of hepatic CYP450 3A4 in pigs with Midazolam probe.The calibration curves were linear over a wide range of concentrations (0.05～25μg/ml),and the detection limit of Midazolam was 0.05μg/ml.The precisions (RSD%,n=5) of within day and day to day were less than 6.5%and 15%,respectively.The pharmacokinetic characteristics of Midazolam in pigs after after oral administration 2 mg/kg were best described by an open two-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows,respectively:t1/2α:0.23±0.07 h,t1/2β:0.30±0.04 h,CL(s):2.10±0.55 L/h,AUC:0.97±0.17μg·h/mL.It is close with results in literature and showed that hepatic CYP 3A4 is acticve in pigs
2 The activity studies of dextromethorphan P450 2D6 probe in pig
The activity of hepatic CYP450 2D6 were investigated with dextromethorphan probe in pig by HPLC method.The pharmacokinetic characteristics of dextromethorphan in pig after oral administration 1 mg/kg were best described by an open one-compartment model with first order absorption rate.The main pharmacokinetic parameters were as follows, respectively:t1/2α0.86±0.24 h,t1/2β2.58±0.22 h,CL(s),4.52±0.41μg·h/mL.it showed that the activity of hepatic CYP450 2D6 is active in health pigs.
3 Study the effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigs
The effects of Doxycycline,Tiamulin and Cefquinome on the activity of hepatic CYP 450 3A4 and 2D6 in pigs was estimated with Midazolam and Dextromethorphan as probe. 24 pigs were randomly divided into control group(administered with physiological saline), Doxycycline-treated group(5mg/kg·bw,i.p.×7 d),Tiamulin-treated group(5mg/kg·bw, i.p.×7 d)and Cefquinome-treated group(1mg/kg·bw,i.p.×7 d).The plasma concentrations of Midazolam and Dextromethorphan were determined by HPLC.The pharmacokinetic parameters were estimated.The results:In the reach about CYP 3A4,Compared with the saline-treated control group,the T1/2βof Midazolam for Doxycycline and Tiamulin groups is were sharply prolonged(p＜0.01),and the Cefquinome group is significantly shorted(p＜0.01).The CL(s) for Doxycycline group is significantly decreased(p＜0.01),the Cefquinnime group is sharply increased.The AUC for Doxycyline group is sharply increased(p＜0.01),the Cefquinnime group is significantly deereased(p＜0.01).It is showed that activity of CYP 450 3A4 could be markedly inhibited by Doxycycline,and Cefquinome could be a strong inducer.In the reach about CYP 2D6,Compared with the control group,the T1/2βof Dextromethorphan for all the groups were sharply prolonged(p＜0.01).The CL(s) for Cefquinnime group is significantly decreased(p＜0.01). The AUC for Cefquinnime group is sharply inereased(p＜0.01).It is indicated that activity of CYP 450 2D6 could be strongly inhibited by Cefquinome.
引文
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