乙酰甲喹在山羊和绵羊体内的药动学及其抗菌后效应研究
摘要
本试验研究了乙酰甲喹(Maquindox)在山羊和绵羊体内的药动学特征,及其对大肠埃希菌、无乳链球菌、金黄色葡萄球菌和沙门氏菌的体外抗菌后效应。
1山羊单剂量快速静注和肌注乙酰甲喹7 mg/kg,7 h内不同时间12次颈静脉采血,高效液相色谱法测定血药浓度。结果表明,(1)乙酰甲喹静注时在山羊体内的药物动力学配置符合无吸收因素一室开放模型。其药-时曲线最佳方程为:C = 14.6547e~(-0.4871t);主要药物动力学参数:消除半衰期t1/2为2.0622 h±0.2645 h,药-时曲线下面积AUC为32.3676μg/mL·h±2.9216μg/mL·h,表观分布容积Vd为0.6427 L/kg±0.0429 L/kg,体清除率CLB为0.2177 L/(kg·h)±0.0193 L/(kg·h)。(2)乙酰甲喹肌注时在山羊体内的药物动力学配置符合有吸收因素一室开放模型。其药-时曲线最佳方程为:C = 19.1709(e~(-0.4830t)– e~(-3.0861t)),主要药物动力学参数:消除半衰期t_(1/2ke)为1.5024 h±0.3430 h,吸收半衰期t_(1/2ka)为0.2617 h±0.1119 h,药-时曲线下面积AUC为30.1562μg/mL·h±5.6303μg/mL·h,消除速率常数kel为0.4830 /h±0.1180 /h ,分布速率常数ka为3.0861 /h±1.2791 /h,药峰值时间t_(max)为0.7772 h±0.2390 h,药峰浓度C_(max)为11.0122μg/mL±2.9387μg/mL,表观分布容积Vd为0.4679 L/kg±0.0659 L/kg,体清除率CL_B为0.2222 L/(kg·h)±0.0436 L/(kg·h)。提示乙酰甲喹在山羊体内分布广泛,消除较快。
2绵羊单剂量快速静注和肌注乙酰甲喹7 mg/kg,7 h内不同时间12次颈静脉采血,高效液相色谱法测定血药浓度。结果表明,(1)乙酰甲喹静注时在绵羊体内的药物动力学配置符合无吸收因素一室开放模型。药-时曲线最佳方程为:C = 10.833e~(-0.3404t);主要药物动力学参数:消除半衰期t1/2为2.0622 h±0.2645 h,药-时曲线下面积AUC为32.3676μg/mL·h±2.9216μg/mL·h,表观分布容积V_d为0.6427 L/kg±0.0429 L/kg,体清除率CL_B为0.2177 L/(kg·h)±0.0193 L/(kg·h)。(2)乙酰甲喹肌注时在绵羊体内的药物动力学配置符合有吸收因素一室开放模型。其药-时曲线最佳方程为:C=25.4404(e~(-0.3723t)– e~(-1.5503t)),主要药物动力学参数:消除半衰期t_(1/2ke)为2.3457 h±0.3028 h,吸收半衰期t1/2ka为0.4122 h±0.0691 h,药-时曲线下面积AUC为69.6577μg/mL·h±5.3173μg/mL·h,消除速率常数kel为0.2999 /h±0.0420 /h ,分布速率常数k_a为1.7290 /h±0.3484 /h,药峰值时间t_(max)为1.2854 h±0.0977 h,药峰浓度C_(max)为14.2367μg/mL±0.7614μg/mL,表观分布容积Vd为0.7204 L/kg±0.0551 L/kg,体清除率CLB为0.2171 L/(kg·h)±0.0165 L/(kg·h)。结果显示,乙酰甲喹在绵羊体内分布广泛,消除较快,但比在山羊体内消除稍慢。
3采用菌落计数法测定了不同浓度下乙酰甲喹对大肠埃希菌、沙门氏菌、金黄色葡萄球菌和无乳链球菌的抗菌后效应(post-antibiotic effect,PAE)。乙酰甲喹在1×MIC～4×MIC浓度范围内对四种细菌均显示不同程度PAE,且PAE值随药物浓度增大而延长。对于大肠埃希菌,除在4×MIC与1×MIC时,乙酰甲喹的PAE间存在极显著差异(P<0.01)外,其余浓度间均存在显著差异(P<0.05);对于沙门氏菌,各浓度间存在显著差异(P<0.05);对于金黄色葡萄球菌和无乳链球菌,除金黄色葡萄球菌在4×MIC与2×MIC无差异(P>0.05)外,其余各浓度间均差异显著(P<0.05)。结果表明,乙酰甲喹能产生明显的PAE,呈现明显的剂量依赖性,这对于临床合理的应用乙酰甲喹具有重要的意义。
The pharmacokineticses of Maquindox in goats and sheep, post-antibiotic effect of Escherichia coli, Salmonella, Staphylococcus aureus and Streptococcus agalactiae were studied in this paper.
1 Twelve goats were devided into two groups and treated with a single dosage of maquindox (7 mg/kg) intravenously and intramuscularly, while the blood samples were collected from vein within 7 hours after giving drug. The concentrations of maquindox in serum were determined by high performance liquid chromatography (HPLC). The results showed: (1) The one-compartment open model with first-order disabsorption factor adequately described concentrations of maquindox in serum disposition after i.v. and the best concentration-time equation was C = 14.6547e~(-0.4871t). The primary pharmacokinetics parameters of maquindox were as follows: t1/2 was 2.0622 h±0.2645 h, AUC was 32.3676μg/mL·h±2.9216μg/mL·h, Vd was 0.6427 L/kg±0.0429 L/kg, CL_B was 0.2177 L/(kg·h)±0.0193 L/(kg·h); (2) The one-compartment open model with first-order absorption factor adequately described concentrations of maquindox in serum disposition after i.m.and the best concentration-time equation was C = 19.1709(e~(-0.4830t)–e~(-3.0861t)). The primary pharmacokinetics parameters of maquindox were as follows: t1/2ke was 1.5024 h±0.3430 h, t1/2ka was 0.2617 h±0.1119 h, AUC was 30.1562μg/mL·h±5.6303μg/mL·h, k_(el) was 0.4830 /h±0.1180 /h, k_a was 3.0861 /h±1.2791 /h, t_(max) was 0.7772 h±0.2390 h, C_(max)x was 11.0122μg/mL±2.9387μg/mL, Vd was 0.4679 L/kg±0.0659 L/kg, and CL_B was 0.2222 L/(kg·h)±0.0436 L/(kg·h). It will be seen that the distribution of maquindox in vivo was abroad and the elimination of maquindox in vivo was rapid.
2 Twelve sheep were devided into two groups and treated with a single dosage of maquindox (7 mg/kg) intravenously and intramuscular, while the blood samples were collected from vein within 7 hours after giving drug. The concentrations of maquindox in serum were determined by high performance liquid chromatography (HPLC). The results showed: (1) The one-compartment open model with first-order disabsorption factor adequately described concentrations of maquindox in serum disposition after i.v. and the best concentration-time equation was 10.833e~(-0.3404t). The primary pharmacokinetics parameters of maquindox were as follows: t_(1/2) was2.0622 h±0.2645 h, AUC was 32.3676μg/mL·h±2.9216μg/mL·h, Vd was 0.6427 L/kg±0.0429 L/kg, CL_B was 0.2177 L/(kg·h)±0.0193 L/(kg·h). (2) The one-compartment open model with first-order absorption factor adequately described concentrations of maquindox in serum disposition after i.m.and the best concentration-time equation was C = 25.4404(e~(-0.3723t)–e~(-1.5503t)). The primary pharmacokinetics parameters of maquindox were as follows: t1/2ke was 2.3457 h±0.3028 h, t1/2ka was 0.4122 h±0.0691 h, AUC was 69.6577μg·mL~(-1)·h±5.3173μg·mL~(-1)·h, kel was 0.2999 /h±0.0420 /h, ka was1.7290 /h±0.3484 /h, tmax was 1.2854 h±0.0977 h, Cmax was 14.2367μg/mL±0.7614μg/mL, Vd was 0.7204 L/kg±0.0551 L/kg, and CLB was 0.2171 L/(kg·h)±0.0165 L/(kg·h). It will be seen that the distribution of maquindox in vivo was abroad and the elimination of maquindox in vivo was rapid.
3 The post-antibiotics effect (PAE) of Maquindox against Escherichia coli, Salmonella, Staphylococcus aureus and Streptococcus agalactiae were determinated by colony counting. The results indicated that the Maquindox which concentration was from 1×MIC to 4×MIC had obvious PAE against four bacterias related above and the longer PAE were induced along with increasing drug concentration. There was greatly significant differences between the concentration of 4×MIC and 1×MIC(P<0.01).In the rest of concentration, there was significant differences(P<0.05). There was significant differences in every concentration of Maquindox against Salmonella, Staphylococcus aureus and Streptococcus agalactiae, but it was no significant differences between 4×MIC and 2×MIC for Staphylococcus aureus.The results indicated that PAEs induced by Maquindox were obvious and depended on the dose of the drug. It should be considered as an important factor in designing dosing schedule of the Maquindox.
1山羊单剂量快速静注和肌注乙酰甲喹7 mg/kg,7 h内不同时间12次颈静脉采血,高效液相色谱法测定血药浓度。结果表明,(1)乙酰甲喹静注时在山羊体内的药物动力学配置符合无吸收因素一室开放模型。其药-时曲线最佳方程为:C = 14.6547e~(-0.4871t);主要药物动力学参数:消除半衰期t1/2为2.0622 h±0.2645 h,药-时曲线下面积AUC为32.3676μg/mL·h±2.9216μg/mL·h,表观分布容积Vd为0.6427 L/kg±0.0429 L/kg,体清除率CLB为0.2177 L/(kg·h)±0.0193 L/(kg·h)。(2)乙酰甲喹肌注时在山羊体内的药物动力学配置符合有吸收因素一室开放模型。其药-时曲线最佳方程为:C = 19.1709(e~(-0.4830t)– e~(-3.0861t)),主要药物动力学参数:消除半衰期t_(1/2ke)为1.5024 h±0.3430 h,吸收半衰期t_(1/2ka)为0.2617 h±0.1119 h,药-时曲线下面积AUC为30.1562μg/mL·h±5.6303μg/mL·h,消除速率常数kel为0.4830 /h±0.1180 /h ,分布速率常数ka为3.0861 /h±1.2791 /h,药峰值时间t_(max)为0.7772 h±0.2390 h,药峰浓度C_(max)为11.0122μg/mL±2.9387μg/mL,表观分布容积Vd为0.4679 L/kg±0.0659 L/kg,体清除率CL_B为0.2222 L/(kg·h)±0.0436 L/(kg·h)。提示乙酰甲喹在山羊体内分布广泛,消除较快。
2绵羊单剂量快速静注和肌注乙酰甲喹7 mg/kg,7 h内不同时间12次颈静脉采血,高效液相色谱法测定血药浓度。结果表明,(1)乙酰甲喹静注时在绵羊体内的药物动力学配置符合无吸收因素一室开放模型。药-时曲线最佳方程为:C = 10.833e~(-0.3404t);主要药物动力学参数:消除半衰期t1/2为2.0622 h±0.2645 h,药-时曲线下面积AUC为32.3676μg/mL·h±2.9216μg/mL·h,表观分布容积V_d为0.6427 L/kg±0.0429 L/kg,体清除率CL_B为0.2177 L/(kg·h)±0.0193 L/(kg·h)。(2)乙酰甲喹肌注时在绵羊体内的药物动力学配置符合有吸收因素一室开放模型。其药-时曲线最佳方程为:C=25.4404(e~(-0.3723t)– e~(-1.5503t)),主要药物动力学参数:消除半衰期t_(1/2ke)为2.3457 h±0.3028 h,吸收半衰期t1/2ka为0.4122 h±0.0691 h,药-时曲线下面积AUC为69.6577μg/mL·h±5.3173μg/mL·h,消除速率常数kel为0.2999 /h±0.0420 /h ,分布速率常数k_a为1.7290 /h±0.3484 /h,药峰值时间t_(max)为1.2854 h±0.0977 h,药峰浓度C_(max)为14.2367μg/mL±0.7614μg/mL,表观分布容积Vd为0.7204 L/kg±0.0551 L/kg,体清除率CLB为0.2171 L/(kg·h)±0.0165 L/(kg·h)。结果显示,乙酰甲喹在绵羊体内分布广泛,消除较快,但比在山羊体内消除稍慢。
3采用菌落计数法测定了不同浓度下乙酰甲喹对大肠埃希菌、沙门氏菌、金黄色葡萄球菌和无乳链球菌的抗菌后效应(post-antibiotic effect,PAE)。乙酰甲喹在1×MIC～4×MIC浓度范围内对四种细菌均显示不同程度PAE,且PAE值随药物浓度增大而延长。对于大肠埃希菌,除在4×MIC与1×MIC时,乙酰甲喹的PAE间存在极显著差异(P<0.01)外,其余浓度间均存在显著差异(P<0.05);对于沙门氏菌,各浓度间存在显著差异(P<0.05);对于金黄色葡萄球菌和无乳链球菌,除金黄色葡萄球菌在4×MIC与2×MIC无差异(P>0.05)外,其余各浓度间均差异显著(P<0.05)。结果表明,乙酰甲喹能产生明显的PAE,呈现明显的剂量依赖性,这对于临床合理的应用乙酰甲喹具有重要的意义。
The pharmacokineticses of Maquindox in goats and sheep, post-antibiotic effect of Escherichia coli, Salmonella, Staphylococcus aureus and Streptococcus agalactiae were studied in this paper.
1 Twelve goats were devided into two groups and treated with a single dosage of maquindox (7 mg/kg) intravenously and intramuscularly, while the blood samples were collected from vein within 7 hours after giving drug. The concentrations of maquindox in serum were determined by high performance liquid chromatography (HPLC). The results showed: (1) The one-compartment open model with first-order disabsorption factor adequately described concentrations of maquindox in serum disposition after i.v. and the best concentration-time equation was C = 14.6547e~(-0.4871t). The primary pharmacokinetics parameters of maquindox were as follows: t1/2 was 2.0622 h±0.2645 h, AUC was 32.3676μg/mL·h±2.9216μg/mL·h, Vd was 0.6427 L/kg±0.0429 L/kg, CL_B was 0.2177 L/(kg·h)±0.0193 L/(kg·h); (2) The one-compartment open model with first-order absorption factor adequately described concentrations of maquindox in serum disposition after i.m.and the best concentration-time equation was C = 19.1709(e~(-0.4830t)–e~(-3.0861t)). The primary pharmacokinetics parameters of maquindox were as follows: t1/2ke was 1.5024 h±0.3430 h, t1/2ka was 0.2617 h±0.1119 h, AUC was 30.1562μg/mL·h±5.6303μg/mL·h, k_(el) was 0.4830 /h±0.1180 /h, k_a was 3.0861 /h±1.2791 /h, t_(max) was 0.7772 h±0.2390 h, C_(max)x was 11.0122μg/mL±2.9387μg/mL, Vd was 0.4679 L/kg±0.0659 L/kg, and CL_B was 0.2222 L/(kg·h)±0.0436 L/(kg·h). It will be seen that the distribution of maquindox in vivo was abroad and the elimination of maquindox in vivo was rapid.
2 Twelve sheep were devided into two groups and treated with a single dosage of maquindox (7 mg/kg) intravenously and intramuscular, while the blood samples were collected from vein within 7 hours after giving drug. The concentrations of maquindox in serum were determined by high performance liquid chromatography (HPLC). The results showed: (1) The one-compartment open model with first-order disabsorption factor adequately described concentrations of maquindox in serum disposition after i.v. and the best concentration-time equation was 10.833e~(-0.3404t). The primary pharmacokinetics parameters of maquindox were as follows: t_(1/2) was2.0622 h±0.2645 h, AUC was 32.3676μg/mL·h±2.9216μg/mL·h, Vd was 0.6427 L/kg±0.0429 L/kg, CL_B was 0.2177 L/(kg·h)±0.0193 L/(kg·h). (2) The one-compartment open model with first-order absorption factor adequately described concentrations of maquindox in serum disposition after i.m.and the best concentration-time equation was C = 25.4404(e~(-0.3723t)–e~(-1.5503t)). The primary pharmacokinetics parameters of maquindox were as follows: t1/2ke was 2.3457 h±0.3028 h, t1/2ka was 0.4122 h±0.0691 h, AUC was 69.6577μg·mL~(-1)·h±5.3173μg·mL~(-1)·h, kel was 0.2999 /h±0.0420 /h, ka was1.7290 /h±0.3484 /h, tmax was 1.2854 h±0.0977 h, Cmax was 14.2367μg/mL±0.7614μg/mL, Vd was 0.7204 L/kg±0.0551 L/kg, and CLB was 0.2171 L/(kg·h)±0.0165 L/(kg·h). It will be seen that the distribution of maquindox in vivo was abroad and the elimination of maquindox in vivo was rapid.
3 The post-antibiotics effect (PAE) of Maquindox against Escherichia coli, Salmonella, Staphylococcus aureus and Streptococcus agalactiae were determinated by colony counting. The results indicated that the Maquindox which concentration was from 1×MIC to 4×MIC had obvious PAE against four bacterias related above and the longer PAE were induced along with increasing drug concentration. There was greatly significant differences between the concentration of 4×MIC and 1×MIC(P<0.01).In the rest of concentration, there was significant differences(P<0.05). There was significant differences in every concentration of Maquindox against Salmonella, Staphylococcus aureus and Streptococcus agalactiae, but it was no significant differences between 4×MIC and 2×MIC for Staphylococcus aureus.The results indicated that PAEs induced by Maquindox were obvious and depended on the dose of the drug. It should be considered as an important factor in designing dosing schedule of the Maquindox.
引文
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