大鼠尿中2-苯甲酰肼叉-1,3-二噻茂烷及其代谢产物定量研究

本文建立了线性梯度洗脱,两波长切换检测和两内标法测定染毒大鼠尿中2苯甲酰肼叉-1.3二噻茂烷(BADYH)及其代谢产物的反相高效液相色谱方法.研究了大鼠ig不同剂量BADYH后,经尿排泄的DADYH及其代谢产物累积量-时间过程.结果表明,BADYH及其代谢产物累积排泄量占染毒总量的39.7％。其中主要代谢产物丙酮缩肝叉1.3二噻茂烷,占23.6％;肼叉1.2二噻茂炼占14.0％     

叶枯灵在大鼠尿内的代谢产物分析

大鼠ig叶枯灵后,用HPLC和TLC分离纯化尿提取液中的叶枯灵及其代谢产物,得到六个组分,经MS和UV初步鉴定为叶枯灵,苯甲酸,马尿酸和三个新化合物:肼叉-1.3-二噻茂烷,乙酰肼叉-1.3-二噻茂烷和丙酮酸缩肼叉-1.3-二噻茂烷,通过对代谢物的化学合成,进一步确证了它们的化学结构。     

农药叶枯灵对大鼠离体灌流肝的影响

农药叶枯灵是一种新型高效有机硫杀菌剂,其化学名为2-苯酰肼叉-1,3噻茂烷,对水稻白叶枯病的防治效果良好,华西医科大学对其毒性已进行了研究(见华西医科大学成立75周年获奖论文集1985;173)。本研究用灌流肝实验模型,对灌流肝流出液的酶活性及Na~+、K~+浓度进行探讨,为代谢研究提供实验资料。     

建立大鼠原位肠-肝灌流模型评价绿原酸的代谢

目的：建立大鼠原位肠-肝灌流模型，运用该模型研究绿原酸在大鼠肠、肝中的代谢转化。方法：采用液相色谱质谱联用（HPLC-MS）法测定大鼠原位肠-肝灌流模型灌流液中绿原酸及其代谢产物咖啡酸、阿魏酸和马尿酸。结果：绿原酸十二指肠给药后，灌流液中主要活性代谢产物为阿魏酸，同时在灌流液中也检测到少量活性代谢产物咖啡酸和大量代谢终产物马尿酸。结论：大鼠原位肠-肝灌流模型适用于绿原酸生物转化和代谢动力学的研究；绿原酸在肠中存在广泛的代谢。     

基于大鼠原位肠-肝血管灌流模型研究甘草酸的代谢

目的研究甘草酸在大鼠体内的肠、肝中的生物转化。方法建立大鼠原位肠-肝血管灌流模型,采用LC-MS/MS方法测定灌流液中的甘草酸和甘草次酸。结果甘草酸在单向肠-肝血管灌流模型中稳态肠提取率和稳态肝提取率分别为(4.2±0.6)%和(28.0±3.0)%,灌流液中未发现代谢物甘草次酸;原位循环肠血管灌流模型中甘草酸的一级吸收速率常数为(0.33±0.06)min-1;甘草酸在大鼠十二指肠给药后,灌流液中主要活性代谢产物为甘草次酸,同时肠腔液也存在大量甘草次酸。结论甘草酸的首过效应明显,口服后其主要被肠道菌群或肝细胞代谢,在肠粘膜细胞仅少量代谢。大鼠原位肠-肝血管灌流模型适用于甘草酸的药动学研究。     

N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯及其代谢产物在大鼠离体肝脏中的代谢动力学

利用大鼠肝脏灌流技术研究了N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯(TMDMC)及其代谢产物在大鼠离体肝脏中的代谢动力学,TMDMC在改良的灌流液中作循环式灌流,于不同时间留取少量灌流液,用高效液相色谱(HPLC)作药物的定量分析,结果显示其在离体灌流肝脏中的清除模型符合两相消除模型,动力学参数表明,TMDMC在肝内的分布较快,其分布半衰期仅为4min,肝脏分布容积为102.4 ml,清除率是0.67ml·min~(-1),清除比率为0.027.灌流2h时,其浓度已下降了73％.与此同时,TMDMC的代谢产物逐渐生成,其中以产物Ⅲ的生成量最大,其最高生成浓度(C_(max))为447.1 μg·ml~(-1),2 h产物Ⅲ的生成总量已达TMDMC灌流量的25.6％.而代谢产物Ⅱ,Ⅵ的生成较少,其C_(max)分别是20.4μg·ml~(-1)和20.7μg·ml~(-1).     

N,N-二甲基-1,2,3-三噻烷-5-胺草酸盐经大鼠肝微粒体的代谢

以大鼠肝微粒体为代谢模型,对沙蚕毒素类杀虫剂-易卫杀(N N-二甲基-1,2,3-三噻烷-5-胺草酸盐)进行了体外代谢观察,结果表明易卫杀经大鼠肝微粒体的代谢速率较快,其主要代谢产物有N,N-二甲基-1,2-二硫环戊烷-4胺(a,沙蚕毒素);N,N-二甲基-1,3双(甲亚磺酰基)-2-丙胺(b);N-甲基-1,2-二硫环戊烷-4-胺(c);硫磺聚合物(d)及甲基氨基丙烷(f),可能的代谢途径为:易卫杀脱掉一个硫原子变成沙蚕毒素;沙蚕毒素脱甲基生成脱甲基产物;沙蚕毒素甲基化后进一步生成N,N-二甲基-1,3-双(甲亚磺酰基)-2-丙胺。     

苯酰肼叉二噻茂烷的显性致死试验

<正> 2-苯酰肼叉-1,3-二噻茂烷(2-benzoyl-hydrazonol-1,3-dithiolane,BHD)是一种新的有机硫杀菌剂,对防治水稻白叶枯病比较有效。为了解其对生殖细胞的可能致突变作用,进行了显性致死试验。 实验选用?昆明种小鼠,体重33—44g。每组10只。染毒组分别ig 4.1,12.3和36.9     

兔血中叶枯灵的代谢产物的分离和鉴定

本文用 RP-HPLC 法从染毒兔血中分离出叶枯灵的两个代谢产物。用标准品核对色谱行为,再经质谱鉴定,证实保留时间 tr=8.07±0.15min,为苯甲酸 S-氧-N-1,3-二噻茂烷酰肼(Benzoicacid s-oxo-N-1,3-dithiolan-2-ylidene hydrazide)。保留时间 tr=16.69±0.10min,为苯甲酸(benzoic acid)。     

农药叶枯灵在大鼠原位灌流肝中的代谢研究

采用反相HPLC、TLC、UV、IR和MS对农药叶枯灵经大鼠原位灌流肝代谢后所形成的代谢产物进行分离和鉴定。结果表明,叶枯灵在大鼠肝脏中进行了广泛的代谢,包括S-氧化作用、水解作用、丙酮酸缩合作用和乙酰化作用,共分离鉴定出5种代谢产物。     

Metabolism of the glutathione conjugate of propachlor by in situ perfused kidneys and livers of rats

1. [1-14C]Propachlor-GSH was perfused at 0.34, 3.4 and 34 mumol/h through the portal vein or the right renal artery of anaesthetized rats with biliary and ureteral cannulas. Urine was the predominant route for elimination of the 14C regardless of the route of perfusion. 2. Mercapturic acid conjugates were found to be the end-products of metabolism of the 14C-propachlor-GSH by rat kidneys and liver, indicating that all enzymes necessary for the catabolism of GSH conjugates to mercapturates were present in each of these tissues. 3. Perfusion of 14C-propachlor-GSH at 34 mumol/h appeared to exceed the metabolic capacity of both liver and kidneys for this substrate. At this dose, parent compound was detected in the bile of portally perfused rats, and the amounts of 14C recovered in bile, kidneys and carcasses of renally perfused rats were greater than when smaller dosages were perfused.     

The metabolism of acitretin and isoacitretin in the in situ isolated perfused rat liver.

1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers. 2. Acitretin undergoes alpha-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver. 3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver. 4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.     

Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring.

The metabolic transformation of the antibronchospastic compound ABC-99 [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] was studied in vitro with a rat liver microsomal preparation containing an NADPH-generating system. Thirty percent of the ABC-99 was metabolized and the only metabolic pathway observed as the oxidation of the 1,3-dithiolane ring. Two distinct sulfoxides were formed diastereoselectively, the trans isomer being the major product in the ratio 7:3. In contrast to the 1,3-dioxolane ring of doxophylline, the 1,3-dithiolane ring of ABC-99 did not undergo oxidative opening through acetal carbon oxidation. Furthermore no N-dealkylation to theophylline was observed. This high regioselectivity in in vitro metabolism was most likely due to the nucleophilicity of the sulfur atom. The diastereoselective sulfoxidation was apparently catalyzed by flavin-dependent monooxygenases, as no effect was observed with CO treatment, whereas selective thermal inactivation significantly reduced the rate of sulfoxidation.     

The metabolism of acitretin and isoacitretin in the in situ isolated perfused rat liver

1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers.

2. Acitretin undergoes α-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver.

3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver.

4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.     

Isolated rat hepatocytes and 9000 g rat liver supernatant as metabolic systems for the study of the pharmacokinetics of barbiturates

1. A method for metabolic studies with isolated rat hepatocytes has been developed. The rate of metabolism of a number of barbiturates has been studied both in hepatocytes and in 9000 g rat liver supernatant suspension. 2. The half-lives and clearance values, relative to heptabarbital, determined in hepatocytes were similar to the values obtained with isolated perfused rat liver. The values obtained with the 9000 g supernatant preparation were not. 3. In respect of metabolites formed, the metabolism of barbiturates in hepatocytes is comparable to that of the intact rat or liver perfusion. The metabolism in the 9000 g supernatant, however, is not.     

T2毒素在灌流大鼠肠肝中的首过效应和代谢动力学

建立并用大鼠在体肠-肝灌流标本研究了T2毒素在大鼠肠肝中的首过效应和代谢转化动力学,T2毒素在大鼠肠肝中的主要代谢产物是HT2,3′-OHHT2和其葡萄糖醛酸结合物,T2毒素具有显著的肠肝首过效应,当毒素(42μg·ml~(-1))由上肠系膜动脉恒速单次灌流(8 ml·min~(-1))肠-肝标本时,穗态肝、肠抽提率分别为0.978和0.454,总有效清除率为7.91 ml·min~(-1),T2毒素在循环灌流大鼠肠-肝标本中的消除半衰期为6.5min,主要代谢产物HT2,3′-OHHT2的生成半衰期分别为8.5和38.5 min,结果表明,T2毒素经消化道中毒后,在肠和肝的首过代谢下能很快地转化为产物,因此,毒素在体内的毒效作用主要由其代谢产物表现出来。