大黄酸对大鼠灌胃高剂量对乙酰氨基酚的代谢和排泄的影响

Effects of rhein on metabolism and excretion in rat ig high-dose paracetamol

目的研究大黄酸对大鼠ig高剂量对乙酰氨基酚代谢、排泄的影响,阐述大黄酸对药物性肝损伤的保护作用及其机制。方法将SD大鼠随机分为对乙酰氨基酚组(2.5 g/kg)和对乙酰氨基酚(2.5 g/kg)联用大黄酸组(125 mg/kg),分别采集两组大鼠血浆、尿液和粪便样品,测定对乙酰氨基酚的体内药物浓度,比较对乙酰氨基酚单用组和联用大黄酸后对乙酰氨基酚的体内药物浓度差异。结果对乙酰氨基酚联合大黄酸后对乙酰氨基酚的药动学行为较单用组有明显改变。与单用比较,联用组对乙酰氨基酚的AUC、C_(max)均有明显降低。尿粪排泄的结果显示对乙酰氨基酚主要以原型、葡萄糖醛酸结合物和硫酸结合物的形式从尿液排泄,48 h内联用组的原型、葡萄糖醛酸结合物和硫酸结合物的尿粪排泄量要高于单用组,表明大黄酸能够促进对乙酰氨基酚的排泄速率。结论大黄酸可以显著影响高剂量对乙酰氨基酚的药动学行为,通过增加对乙酰氨基酚的排泄而降低对乙酰氨基酚在体内的暴露,从药动学的角度阐释大黄酸对药物性肝损伤的保护作用。

Objective To study the effects of rhein on metabolism and excretion in rats ig high-dose acetaminophen, and to elucidate the protective mechanism of rhein on drug-induced liver injury. Methods SD rats were randomly divided into paracetamol group （2.5 g/kg） and combination of paracetamol （2.5 g/kg） with rhein （125 mg/kg） group. The plasma, urinary and excreta samples were collected to determine the concentrations of paracetamol. Then compare the difference of the concentration of paracetamol in the paracetamol alone and combination with rhein group.Results Pharmacokinetic parameters of paracetamol combined with rhein were significantly different with thoset in the single group. Compared with paracetamol alone, the AUC andCmax of paracetamol in combination group were significantly decreased. Urinary and fecal excretion results showed that paracetamol was mainly excreted in urine in the form of prototypes, glucuronide conjugates, and sulfuric acid conjugates. The urinary and fecal excretion of paracetamol prototypes, glucuronide conjugates, and sulfuric acid conjugates in the combination with rhein group were significantly higher than those in the single administration group in 48 h, indicating that the urinary and fecal excretion rate of acetaminophen was increased after administration of rhein.ConclusionRhein can significantly affect the pharmacokinetics of paracetamol, and reduce the exposure of acetaminophenin vivo by increasing the excretion of paracetamol, elucidating its hepatoprotective role from pharmacokinetic perspective.