葡萄糖醛酸内酯对小鼠对乙酰氨基酚代谢的影响

目的:研究葡萄糖醛酸内酯对小鼠的对乙酰氨基酚代谢的影响.方法:采用HPLC测定给药后不同时间血浆药物及其代谢产物浓度,求得药物动力学参数.结果:与对照组相比,葡萄糖醛酸内酯对小鼠的对乙酰氨基酚的代谢速率和结合代谢均无影响.结论:单用葡萄糖醛酸内酯不能发生结合解毒作用.     

肝泰乐注射液对小鼠体内对乙酰氨基酚代谢作用的研究

目的：研究肝泰乐对小鼠体内对乙酰氨基酚代谢的影响。方法：HPLC测定给药后不同时间血红及其代谢产物浓度，求得药动学参数。结果：与对照组相比，肝泰乐对小鼠体内对乙酰氨基酚的代谢速率和结合代谢均无明显影响。结论：肝泰乐不能作为治疗肝炎的主药，单用肝泰对解毒作用影响不大。     

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

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。     

葡萄糖醛酸内酯体系制备的褐藻胶凝胶特性的研究

目的建立葡萄糖醛酸内酯体系,制作褐藻酸钙凝胶食品。方法采用葡萄糖醛酸内酯体系缓慢释放钙离子。结果凝胶体系受钙离子、M/G以及葡萄糖醛酸内酯的量影响很大。随着钙离子浓度的增加,体系开始凝胶的时间逐渐缩短,贮藏模量(G′)、损耗模量(G″)、凝胶强度、复合黏度都逐渐增大;随着M/G的增加,G′、G″和凝胶强度都逐渐减少,而tanδ和凝胶时间逐渐增加;在褐藻酸钙凝胶形成过程中随着葡萄糖醛酸内酯的增加,凝胶点出现的时间逐渐缩短,对完全形成凝胶后的G′、G″和凝胶强度影响不大。结论葡萄糖醛酸内酯体系制备的褐藻胶凝胶结构比较均匀,对制作褐藻胶凝胶食品有利。     

苯巴比妥钠对小鼠醋氨酚代谢的影响

目的研究小鼠醋氨酚（Ａｃｅ）的有关药代动力学及苯巴比妥钠（Ｐｈｅ）对其的影响。方法给正常小鼠和Ｐｈｅ５０ｍｇ·ｋｇ－１ｉｐ７ｄ的小鼠,尾静脉注射Ａｃｅ１００ｍｇ·ｋｇ－１,用ＨＰＬＣ法测定血浆Ａｃｅ及尿液Ａｃｅ、葡萄糖醛酸—Ａｃｅ（ＧＡ）和硫酸—Ａｃｅ（ＳＡ）含量,计算机自动曲线拟合,计算比较其有关药代动力学参数及尿液代谢产物累积排泄量。结果小鼠Ａｃｅ血浆浓度量－时关系曲线呈一房室模型,Ｔ１２为１３．９±０．５５ｍｉｎ,ＣＬ为（０．０４０３２±０．００３８２）Ｌ·ｋｇ－１·ｍｉｎ－１,９ｈ尿液Ａｃｅ、ＧＡ和ＳＡ总累积排泄量为给药量的５４．０％±６．２１％。经Ｐｈｅ诱导后,ＡｃｅＴ１２缩短２７．７％,ＣＬ增加２５．２％,尿液ＧＡ减少１９．３％（Ｐ＜０．０５）。结论至少在ＩＣＲ和昆明种小鼠,Ａｃｅ除与葡萄糖醛酸和硫酸结合外,还有其它重要代谢途径。Ｐｈｅ预处理明显加快小鼠血浆Ａｃｅ消除,但该作用与葡萄糖醛酸和硫酸结合代谢反应无关。     

尿苷二磷酸葡萄糖醛酸转移酶的转录调节与疾病相关性的研究进展

葡萄糖醛酸结合反应是体内重要的Ⅱ相代谢途径,主要由尿苷二磷酸葡萄糖醛酸转移酶（ UGT ）催化。尿苷二磷酸葡萄糖醛酸转移酶能参与多种内源性物质如胆红素、胆汁酸、甲状腺激素等的代谢,也能参与多种药物如阿片类镇痛药、非甾体抗炎药等药物的代谢,在代谢解毒方面起着重要作用。近年来对尿苷二磷酸葡萄糖醛酸转移酶的研究越来越深入,尿苷二磷酸葡萄糖醛酸转移酶与不同疾病的研究受到普遍关注。本文就转录因子介导的尿苷二磷酸葡萄糖醛酸转移酶的分子调节机制及其与不同疾病的相关性研究进行综述。     

穿心莲内酯磺化物E在大鼠体内的代谢及代谢动力学研究

目的:对穿心莲内酯磺化物E在大鼠体内的代谢及代谢动力学进行研究。方法:大鼠分别口服、静注穿心莲内酯磺化物E后,采用LC-MS/MS法测定血浆中原型药物浓度,并估算其相应的药代动力学参数。采用LC-MS/MS法分析鉴定给药后大鼠血浆、尿液、胆汁和粪便中的代谢物。结果:口服给药后,穿心莲内酯磺化物E在大鼠体内吸收较为迅速,但绝对生物利用度仅为0.16%,并迅速从体内消除。进一步的代谢研究发现,静注和口服给药后在大鼠体内的主要代谢物分别为脱水产物,谷胱甘肽结合物及葡萄糖醛酸结合物,其在血浆中的主要存在形式为原型药物和脱水产物。结论:口服给药后,穿心莲内酯磺化物E以原型药物的形式吸收进入体内,并在体内进一步代谢。上述研究结果提示对穿心莲内酯C-19位的羟基进行磺化虽然提高了其水溶性,但降低了其口服生物利用度。     

黄芩素在正常及早期肝纤维化模型小鼠体外肝、肠微粒体中Ⅱ相代谢差异

目的考察肝纤维化模型小鼠肝、肠微粒体对黄芩素体外葡萄糖醛酸化代谢影响和酶促反应动力学研究。方法小鼠每周3次灌胃20%CCl4油溶液,持续6周,检测血清肝功能指标ALT和AST,ELISA试剂盒检测血清中HA,天狼猩红染色和免疫组化染色α-SMA评估肝纤维化模型。检测正常和肝纤维小鼠肠道内容物β-葡萄糖醛酸苷酶活性,同时建立小鼠肝、肠微粒体孵育体系对黄芩素葡萄糖醛酸化反应的酶促反应动力学进行研究,评估其代谢动力学类型,并对比在正常和肝纤维化模型中最大反应速率(Vmax)和米氏常数(Km)。结果经过6周CCl4诱导后,模型组的血清、病理和免疫组化检测结果显示肝纤维化模型复制成功。体外实验结果显示,黄芩素在小鼠肝微粒体中的代谢方式符合米氏方程,而在肠微粒体中属于底物抑制型。与正常组相比,黄芩素在肝纤维化后的肝微粒体中的代谢速率要显著提高(P<0.01),而在肠微粒体中则相反,但差异无统计学意义,同时发现肝纤维化后肠道菌群中的β-葡萄糖醛酸苷酶活性要显著高于正常组(P<0.01)。结论肝纤维化状态对葡萄糖醛酸苷转移酶等Ⅱ相代谢酶的活性带来显著的改变,这值得我们关注肝纤维化疾病状态下药物的代谢特征和临床疗效,促进安全合理用药。     

LC/MSn鉴定咖啡酸在大鼠体内的代谢产物

目的研究咖啡酸（CA）在大鼠体内的代谢产物。方法大鼠灌胃（50mg·kg^-1）给予CA后采集0～4h尿样,用电喷雾离子阱多级质谱法对CA在大鼠体内的代谢产物进行分析。结果大鼠灌胃给予CA后,在体内可测到2个原形药的甲基化代谢物、2个原形药的单葡萄糖醛酸结合物、1个原形药的双葡萄糖醛酸结合物、2个原形药的单硫酸结合物、2个甲基化物的葡萄糖醛酸结合物和2个甲基化物的硫酸结合物。结论CA在大鼠体内广泛代谢,其代谢物的结构有待于进一步分析后确证。     

LC/MSn鉴定咖啡酸在大鼠体内的代谢产物

目的 研究咖啡酸（CA）在大鼠体内的代谢产物。方法 大鼠灌胃（50 mg·kg-1）给予CA后采集0 ~ 4 h尿样,用电喷雾离子阱多级质谱法对CA在大鼠体内的代谢产物进行分析。结果 大鼠灌胃给予CA后,在体内可测到2个原形药的甲基化代谢物、2个原形药的单葡萄糖醛酸结合物、1个原形药的双葡萄糖醛酸结合物、2个原形药的单硫酸结合物、2个甲基化物的葡萄糖醛酸结合物和2个甲基化物的硫酸结合物。结论 CA在大鼠体内广泛代谢,其代谢物的结构有待于进一步分析后确证。     

Dissociation of increased sulfation from sulfate replenishment and hepatoprotection in acetaminophen-poisoned mice by N-acetylcysteine stereoisomers

N-Acetylcysteine stereoisomers were compared for their ability to alter the sulfation and hepatotoxicity of acetaminophen. The clinically used L-isomer increased urinary excretion of inorganic sulfate 2-3 fold and prevented liver injury, but failed to increase acetaminophen sulfation in mice. Conversely, the nonphysiologic D-isomer failed to increase urinary excretion of inorganic sulfate or prevent hepatotoxicity, but increased acetaminophen sulfation appreciably (by 39%). The basis of the incongruence between changes in the availability of inorganic sulfate and the sulfation of acetaminophen is not known. These data indicate that a modest increase in acetaminophen sulfation, occurring alone following N-acetylcysteine treatment, is insufficient to explain the profound efficacy of the antidote in mice, and further suggest that this holds true for other species, such as humans, that are comparatively poor in the sulfoconjugation of acetaminophen.     

甘草酸对小鼠安替比林及醋氨酚代谢的影响

目的研究甘草酸是否诱导小鼠肝细胞增殖及其对安替比林和醋氨酚代谢的影响。方法给小鼠甘草酸５０ｍｇ·ｋｇ－１或等量注射用水灌胃７ｄ后，比较两者间安替比林和醋氨酚有关药代动力学参数及肝ＤＮＡ含量和肝／体重比的差异。结果与对照组相比，甘草酸组小鼠安替比林Ｔ１２缩短４５３％，ＣＬ增加４３６％（Ｐ＜００５）；醋氨酚Ｔ１２延长５４６％，ＣＬ降低２９３％（Ｐ＜００５），尿液葡萄糖醛酸 醋氨酚含量减少１１８％（Ｐ＜００５）；肝ＤＮＡ含量及肝／体重比无明显改变。结论甘草酸能诱导小鼠安替比林代谢，抑制醋氨酚代谢，对肝细胞增殖无影响     

Effects of butylated hydroxyanisole on acetaminophen hepatotoxicity and glucuronidation in vivo

The present study examined the effects of butylated hydroxyanisole (BHA) on acetaminophen-induced hepatotoxicity and metabolism in vivo with emphasis on possible changes in the glucuronidation pathway. Female Swiss-Webster mice received BHA in the diet (1% w/w) for 12 days (600 to 800 mg/kg/day). BHA prevented acetaminophen hepatotoxicity (600 mg/kg, ip), based on serum alanine and aspartate aminotransferase activities and histopathological examination. The rate of elimination of acetaminophen from blood was 10-fold higher in BHA-fed mice (clearance, 49 ml/min/kg) than in controls (4.4 ml/min/kg). In general, the urinary metabolite excretion patterns in control and BHA-treated mice were the same. However, the rates of acetaminophen conjugation via the sulfation, glucuronidation, and mercapturic acid pathways were enhanced with the rate of glucuronide formation, the major biotransformation pathway of acetaminophen, increased sevenfold in BHA-treated mice (0.041 min-1) compared to controls (0.006 min-1). BHA increased hepatic UDP-glucuronosyltransferase activity twofold, as well as hepatic UDP-glucuronic acid concentrations. In addition, after acetaminophen administration, UDP-glucuronic acid in BHA-treated mice was depleted to a lesser extent and returned to control values more rapidly than in untreated animals. BHA had a similar but less pronounced effect on hepatic glutathione levels. The findings indicate that the rate of acetaminophen glucuronidation is increased in vivo during BHA feeding to mice. This effect appears to play a role in the enhanced excretion of acetaminophen as well as protection against acetaminophen-induced hepatotoxicity.     

Effect of a concomitant single dose of ethanol on the hepatotoxicity and metabolism of acetaminophen in mice

A concomitant single dose of ethanol (1 g/kg) protected mice from hepatic injury induced by acetaminophen (250 mg/kg) as evidenced by the lowering of plasma transaminases. Pharmacokinetic studies with [¹⁴C]acetaminophen indicated that ethanol enhanced the initial blood concentrations of radiolabel and its rate of elimination. A tissue distribution study suggested that these effects were probably due to an ethanol-induced inhibition of the biliary clearance of acetaminophen from the blood. Examination of the urinary and biliary metabolites indicated that ethanol inhibited the excretion of the degradation products derived from the glutathione-deactivated hepatotoxic acetaminophen intermediate. The decrease in acetaminophen induced hepatotoxicity was therefore attributed to an inhibitory effect of ethanol on the biotransformation of acetaminophen to the toxic intermediate.     

乙酰胡椒乙胺对扑热息痛肝脏毒性的保护作用

目的：研究乙酰胡椒乙胺(piperoethyl acetyl amine, PAA)对扑热息痛(acetaminophen, AP)肝脏毒性的保护作用及其机制。方法：小鼠ig PAA后ip AP, 检测小鼠肝脏的损害程度,高效液相法检测血中AP含量,检测小鼠肝细胞色素P-450含量。结果：PAA明显降低AP所致的小鼠血清转氨酶升高,减轻肝脏病理损害,阻止肝内谷胱甘肽下降,增加肝细胞色素P-450含量,血中AP浓度明显降低。结论：PAA对AP中毒小鼠有明显肝保护作用。     

拉米夫定联合肝泰乐治疗慢性乙型肝炎肝纤维化疗效观察

目的：观察拉米夫定联合肝泰乐治疗慢性乙型肝炎肝纤维化的疗效。方法：124例慢性乙肝患者随机分为实验组（A组,n=64）和对照组（B组,n=60）,两组治疗前的基线资料无统计学差异（P〉0.05）。对照组给予拉米夫定100mg,1次/d;实验组除按上述方法服用拉米夫定外,给予肝泰乐0.2g,3次/d,疗程1a。观察治疗前后乙肝病毒学标记物、肝功能、HBV-DNA、肝纤维化指标的改变。结果：治疗后A组和B组均有良好的病毒学应答,两组比较无统计学差异（P〉0.05）;实验组和对照组的肝功能指标均有明显改善,但实验组肝功能的指标的改善优于对照组,有统计学差异（P〈0.05）。结论：拉米夫定联合肝泰乐对慢性乙型肝炎肝纤维化的改善具有优于单一用药的疗效,值得进一步推广。     

Factors influencing circadian rhythms in acetaminophen lethality

Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.     

N-acetylcysteine-induced inhibition of gastric emptying: A mechanism affording protection to mice from the hepatotoxicity of concomitantly administered acetaminophen

Swiss Webster male mice, 22 ± 3 g, killed 17–18 h following the concomitant oral administration of acetaminophen (350 mg/kg) and N-acetylcysteine (NAC, 100–500 mg/kg, treated) had statistically significant lower plasma transaminases (GOT and GPT) than control mice (acetaminophen + water). Possible mechanisms underlying this protective effect of NAC were examined. NAC (500 mg/kg) reduced [¹⁴C]acetaminophen-derived radioactivity in the blood and tissues but increased the percentage of the dose in the gastrointestinal tract. Depletion of hepatic sulphydryl compounds below 75% of the control value was prevented by NAC treatment, whereas urinary excretion of mercapturate and sulfate, metabolites derived from sulphydryls, were proportionally increased and excretion of unchanged drug was decreased by NAC. Absorption of acetaminophen from the small intestine was prevented by NAC and this was attributed to an inhibition in gastric emptying. Since all changes observed following NAC treatment could be attributed to inhibition of gastric emptying, it was considered the major mechanism responsible for affording in mice protection from acetaminophen-induced hepatocellular damage following concomitant oral administration.