海洋硫酸多糖916对普伐他汀在大鼠体内药代动力学影响
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摘要
普伐他汀是胆固醇合成过程中限速酶HMG-CoA还原酶的抑制剂,临床用于治疗高脂血症,并用于降低心脑血管疾病、肾病综合征、糖尿病性高脂血症的发生率。硫酸多糖药物916具有良好的抗动脉粥样硬化活性,目前,已经国家药品监督管理局批准作为I类新药进入临床研究。为了治疗混合型高血脂症,临床常将他汀类药物与其它类的降血脂药和抗动脉粥样硬化药物联合使用。本实验以大鼠为对象研究916与普伐他汀合用时对普伐他汀药代动力学的影响,为临床安全用药提供依据和参考。
1.建立了高效液相色谱分析体内普伐他汀含量的方法。生物样品预处理采用乙腈沉淀蛋白与固相萃取联合的方法;流动相为乙腈和磷酸二氢钠缓冲盐(pH 3.0),色谱柱为C-l8反相柱;考察了方法的精密度、重现性和回收率,实验证明该方法灵敏度高,精密度和重现性较好,可用于血浆、肝脏、肌肉中普伐他汀的含量测定。
2.采用口服灌胃给药,研究了合用药物916后对普伐他汀在雄性和雌性大鼠体内药动学的影响。结果发现合用916后,在雄、雌性大鼠体内普伐他汀的达峰血药浓度CMax显著性降低(P<0.05),但AUC0→∞无显著性变化(P>0.05)。同时雄性大鼠体内普伐他汀t1/2显著增加,ke显著降低(P<0.05),雌性大鼠体内t1/2和ke虽有所降低但无显著性差异(P>0.05)。
3.采用大鼠在体小肠回流试验法,研究了合用药物916后对普伐他汀吸收情况的影响。结果发现,普伐他汀与药物916合用后Ka值减小(P<0.05),普伐他汀的吸收百分率无显著性差异(P>0.05)。推测药物916影响了普伐他汀在小肠部位的吸收速度,使普伐他汀的吸收延迟,但对总吸收百分率无显著影响。
4.研究了单剂量灌胃及合用药物916后对普伐他汀在肝脏和肌肉中的分布的影响。结果发现合用916后0.4h肝脏中普伐他汀含量较单用时显著降低(P<0.05),1.5h肝脏中普伐他汀含量无显著性变化(P>0.05),4h时肝脏中普伐他汀浓度显著性升高(P<0.05)。肌肉中普伐他汀含量在不同时间点虽有所降低但无显著性差异(P>0.05)。
Pravastatin (PV) is a cholesterol-lowering inhibitor of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, has been indicated for the treatment of hypercholesterolemia and the prevention of cardiovascular disease, diabetes mellitus, and renal disease. Marine Sulfated Polysaccharide 916 has been reported with good anti-atherosclerosis activity and authorized to go into clinical study as I level new drug by National Drug and Foods Administration. In order to treat combined hyperlipidemia, statins species and other cholesterol-lowering drugs are usually used together for treating patients. In order to provide reference about safety medication in clinic, the influences of 916 on the pharmacokinetics of PV in rats were studied.
1. To detect PV in biological samples, high performance liquid chromatography analysis method was established. In this paper, protein precipitation by acetonitrile combined with SPE method is selected for the pretreatment of biological samples. The analysis was performed using a C-18 reverse-phase column with mobile phase of Na2HPO4 buffer solution (pH=3.0) and acetonitrile. The precision, reproducibility and recovery of PV in biological samples were tested. This method was proved to have high sensitivity, the precision and reproducibility was better. This method can be used to detect the concentration of PV in plasma, liver and muscle.
2. The influence of 916 on the pharmacokinetics of PV in male and female rats was investigated. When in combination with 916 , the highest plasma concentration(CMax) of PV were decreased than those when PV was administered alone(P<0.05), but AUC0→∞was not significantly effected (P>0.05). Meanwhile in male rats, t1/2 was increased, ke was decreased (P<0.05), but in female rats, t1/2 and ke weren’t changed significantly (P>0.05).
3. To explore the influence of 916 on the intestinal absorption of PV, the rat intestinal recirculating method in situ was utilized. When in combination with 916, the absorption Constants (Ka) was lower than those when PV was administered alone (P<0.05), but the percent absorption was not significant effected (P>0.05).The results suggested that 916 had effects on the rate of absorption of PV from the intestine, delayed the absorption of PV, but the total percent absorption wasn’t significant effected.
4. The influence of 916 on the distribution of PV in liver and muscle was investigated. When in combination with 916,the concentration of PV in liver at 0.4h was significant decreased(P<0.05), the concentration of PV in liver at 1.5h was not significantly effected (P>0.05) , but the concentration of PV in liver at 4h was significantly increased. The concentration of PV in muscle was not significantly effected (P>0.05).
1.建立了高效液相色谱分析体内普伐他汀含量的方法。生物样品预处理采用乙腈沉淀蛋白与固相萃取联合的方法;流动相为乙腈和磷酸二氢钠缓冲盐(pH 3.0),色谱柱为C-l8反相柱;考察了方法的精密度、重现性和回收率,实验证明该方法灵敏度高,精密度和重现性较好,可用于血浆、肝脏、肌肉中普伐他汀的含量测定。
2.采用口服灌胃给药,研究了合用药物916后对普伐他汀在雄性和雌性大鼠体内药动学的影响。结果发现合用916后,在雄、雌性大鼠体内普伐他汀的达峰血药浓度CMax显著性降低(P<0.05),但AUC0→∞无显著性变化(P>0.05)。同时雄性大鼠体内普伐他汀t1/2显著增加,ke显著降低(P<0.05),雌性大鼠体内t1/2和ke虽有所降低但无显著性差异(P>0.05)。
3.采用大鼠在体小肠回流试验法,研究了合用药物916后对普伐他汀吸收情况的影响。结果发现,普伐他汀与药物916合用后Ka值减小(P<0.05),普伐他汀的吸收百分率无显著性差异(P>0.05)。推测药物916影响了普伐他汀在小肠部位的吸收速度,使普伐他汀的吸收延迟,但对总吸收百分率无显著影响。
4.研究了单剂量灌胃及合用药物916后对普伐他汀在肝脏和肌肉中的分布的影响。结果发现合用916后0.4h肝脏中普伐他汀含量较单用时显著降低(P<0.05),1.5h肝脏中普伐他汀含量无显著性变化(P>0.05),4h时肝脏中普伐他汀浓度显著性升高(P<0.05)。肌肉中普伐他汀含量在不同时间点虽有所降低但无显著性差异(P>0.05)。
Pravastatin (PV) is a cholesterol-lowering inhibitor of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, has been indicated for the treatment of hypercholesterolemia and the prevention of cardiovascular disease, diabetes mellitus, and renal disease. Marine Sulfated Polysaccharide 916 has been reported with good anti-atherosclerosis activity and authorized to go into clinical study as I level new drug by National Drug and Foods Administration. In order to treat combined hyperlipidemia, statins species and other cholesterol-lowering drugs are usually used together for treating patients. In order to provide reference about safety medication in clinic, the influences of 916 on the pharmacokinetics of PV in rats were studied.
1. To detect PV in biological samples, high performance liquid chromatography analysis method was established. In this paper, protein precipitation by acetonitrile combined with SPE method is selected for the pretreatment of biological samples. The analysis was performed using a C-18 reverse-phase column with mobile phase of Na2HPO4 buffer solution (pH=3.0) and acetonitrile. The precision, reproducibility and recovery of PV in biological samples were tested. This method was proved to have high sensitivity, the precision and reproducibility was better. This method can be used to detect the concentration of PV in plasma, liver and muscle.
2. The influence of 916 on the pharmacokinetics of PV in male and female rats was investigated. When in combination with 916 , the highest plasma concentration(CMax) of PV were decreased than those when PV was administered alone(P<0.05), but AUC0→∞was not significantly effected (P>0.05). Meanwhile in male rats, t1/2 was increased, ke was decreased (P<0.05), but in female rats, t1/2 and ke weren’t changed significantly (P>0.05).
3. To explore the influence of 916 on the intestinal absorption of PV, the rat intestinal recirculating method in situ was utilized. When in combination with 916, the absorption Constants (Ka) was lower than those when PV was administered alone (P<0.05), but the percent absorption was not significant effected (P>0.05).The results suggested that 916 had effects on the rate of absorption of PV from the intestine, delayed the absorption of PV, but the total percent absorption wasn’t significant effected.
4. The influence of 916 on the distribution of PV in liver and muscle was investigated. When in combination with 916,the concentration of PV in liver at 0.4h was significant decreased(P<0.05), the concentration of PV in liver at 1.5h was not significantly effected (P>0.05) , but the concentration of PV in liver at 4h was significantly increased. The concentration of PV in muscle was not significantly effected (P>0.05).
引文
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