α-与β-甘草酸在小鼠体内分布的研究

目的 :探讨甘草酸 (glycyrrhizicacid ,GL)的两个差向异构体α GL和 β GL在小鼠体内的分布及其特征。方法 :运用HPLC UV法检测小鼠单次ivα GL或 β GL5 3mg·kg-1后 5、15、30、6 0和 180min时体内各组织脏器中的药物含量 ,比较、评价两者的分布差异及特征。结果 :α GL和 β GLiv后分布迅速 ,除血外 ,肝中含量最高 ,肺、肾、脂肪、心、卵巢、肠、脾、睾丸、肌肉中药物含量依次减小 ,脑中最低 ;肠肝循环的第二峰现象出现在 30min时 ;α GLiv后早期肝含量显著高于 β GL ,血及其余组织脏器药物含量明显低于 β GL或与其相近 ;随时间的延长药物含量迅速降低的同时肠浓度渐高 ,至 180min时α GL各组织脏器 (除肠外 )药物浓度接近或低于检测限 ,β GL则仍维持较高浓度 ,是峰值的 30 %～ 70 %。结论 :小鼠ivα GL后在体内呈肝分布特异性 ,转化成GA的速率高于 β GL ,无组织蓄积 ;而 β GL在体内分布广泛 ,代谢较慢 ,有蓄积的可能     

18α-甘草酸保肝药理作用研究近况

18α-甘草酸(甘草酸二铵,18α-GL)是通常所说的甘草酸(即18β-甘草酸,18β-GL)的差向异构体。18α-GL对急、慢性免疫性肝损伤以及多种化学性肝损伤动物模型均具有显著的保护肝脏作用。但从目前动物实验研究资料分析,尚不足以判定18α-GL的保肝作用强于18β-GL。该文综述了近年来18α-GL在体内外动物实验模型中抗急、慢性肝损伤作用以及与18β-GL保肝作用的比较等方面的研究近况。     

甘草酸-低分子壳聚糖偶联物大鼠体内组织分布研究

目的：研究甘草酸-低分子壳聚糖（GA-LMWC）偶联物在大鼠体内组织分布特征,探讨GA-LMWC偶联物作为肾靶向药物的可行性。方法：将甘草酸溶液和GA-LMWC偶联物溶液分别经尾静脉注射按剂量10 mg·kg^-1给予SD大鼠,并于给药后1,4,8 h取各组织（心、肝、脾、肺、肾）,采用HPLC测定各组织（心、肝、脾、肺、肾）中甘草酸的含量。结果：大鼠尾静脉注射GA-LMWC偶联物后1,4,8 h在肾脏中的分布较甘草酸组显著提高,分别为甘草酸组的1.34倍（P<0.05）、1.46倍（P<0.001）和2.83倍（P<0.01）;在肝脏和脾脏的分布较甘草酸组显著降低（P<0.01）。结论：与游离甘草酸相比,GA-LMWC偶联物改变了甘草酸大鼠体内分布特征,显著增加了GA在肾脏的分布,延长了其肾脏滞留时间,增强了甘草酸的肾脏靶向性。     

18α-甘草酸和18β-甘草酸抗大鼠肝纤维化作用比较研究

目的以γ-干扰素(IFN-γ)为阳性对照药,比较研究18α-甘草酸(18α-GL)、18β-甘草酸(18β-GL)的抗大鼠肝纤维化作用。方法以二甲基亚硝胺(DMN)腹腔注射诱导大鼠肝纤维化模型,染毒开始及染毒后5周分别用18-αGL,18-βGL,IFN-γ预治疗和治疗肝纤维化。观察各组肝羟脯氨酸(HyP)、血清透明质酸(HA)水平,血清生化指标、病理及肝纤维化程度。结果与IFN-γ比较,18-αGL,18β-GL差相异构体预治疗组和治疗组抗肝纤维化作用与其相近,治疗组明显优于染毒对照组;18α-GL治疗组明显优于18β-GL组。结论18-αGL,18β-GL差相异构体有较好的抗肝纤维化作用,且18α-GL明显优于18β-GL。     

18α-甘草酸和18β-甘草酸抗大鼠肝纤维化作用比较研究

目的以γ-干扰素(IFN-γ)为阳性对照药,比较研究18α-甘草酸(18α-GL)、18β-甘草酸(18β-GL)的抗大鼠肝纤维化作用。方法以二甲基亚硝胺(DMN)腹腔注射诱导大鼠肝纤维化模型,染毒开始及染毒后5周分别用18-αGL,18-βGL,IFN-γ预治疗和治疗肝纤维化。观察各组肝羟脯氨酸(HyP)、血清透明质酸(HA)水平,血清生化指标、病理及肝纤维化程度。结果与IFN-γ比较,18-αGL,18β-GL差相异构体预治疗组和治疗组抗肝纤维化作用与其相近,治疗组明显优于染毒对照组;18α-GL治疗组明显优于18β-GL组。结论18-αGL,18β-GL差相异构体有较好的抗肝纤维化作用,且18α-GL明显优于18β-GL。     

18α-甘草酸固体脂质纳米粒的药动学研究

目的 对18α-GL固体脂质纳米粒(18α-GL-SLN)的药动学进行研究。方法 在大鼠股静脉和肝脏同时植入探针,尾静脉给药后,同步微透析采样10 h,HPLC测定透析液中18α-GL的浓度,推算血液及肝脏中真实18α-GL药物浓度,拟合药-时曲线,计算药动学参数,并进行统计分析。结果 大鼠尾静脉给予18α-GL-SLN和18α-GL后血液和肝脏的主要药动学参数C_max、AUC_0→T(n)、AUC_extra和MRT差异均有统计学意义。与18α-GL水溶液相比,18α-GL-SLN的血液C_max显著降低,肝脏C_max显著升高,MRT显著延长,AUC显著增高。结论 18α-GL-SLN给药后药物在大鼠肝脏中的浓度显著升高,存留时间显著延长,提示18α-GL-SLN具有显著的肝脏靶向特性。     

海星甾醇琥珀酸酯(A1998)脂肪乳静脉给药后在大鼠体内的组织分布

目的:研究海星甾醇琥珀酸酯(3β-羟基雄甾-5烯-17酮琥珀酸酯,A1998)脂肪乳经静脉给药后在大鼠体内的组织分布经时变化规律.方法:大鼠单次静脉注射20 mg·kg-1 A1998脂肪乳后,分别于不同时间点剖取各组织脏器,采用HPLC柱前衍生法测定大鼠各组织脏器药物含量.结果:A1998在大鼠体内主要分布于肺、肝、脾等器官,给药后15 min,测得肺脏药物含量最高(32.73±3.87)μg·g-1,脾脏(23.47±8.04)μg·g-1及肝脏(14.87±1.63)μg·g-1次之,均远高于同时间点大鼠血药浓度.A1998在上述3脏器中药物浓度维持时间亦久,至给药36 h后仍能检测出较高浓度,分别为(4.37±2.74),(4.69±2.37)及(8.30±5.96)μg·g-1.静注A1998后心脏及肾脏中药物浓度的经时变化与同时间点血药浓度相似.在胃、小肠、子宫、卵巢、体脂中未检测到药物分布.结论:大鼠单次静脉注射20 mg·kg-1 A1998脂肪乳后,药物在血浆中消除迅速,并快速分布于各组织.A1998在大鼠体内的组织分布具有较强的选择性,各组织中药物浓度经时变化结果提示对肺、肝、脾等脏器具有高度的亲和力.     

18α—甘草酸抗大鼠肝纤维化实验研究

目的 研究18α-甘草酸(18α-GL)及γ-干扰素(IFN-γ)的抗肝纤维化作用。方法 以二甲基亚硝胺(DMN)腹腔注射诱导大鼠肝纤维化模型,染毒开始及染毒后5WK分别用18α-GL和IFN-γ预治疗和治疗肝纤维化。与正常组比较,观察各组病理及肝纤维化程度。结果180α-GL预治疗和治疗组纤维化程度与IFN-γ组相近,且明显小于染毒对照组,肝羟脯氨酸(HYP)、血清透明质酸(HA)较染毒组明显降低。结论18α-GL有较好的抗纤维化作用。     

甘草酸二铵对动物血清胆碱酯酶的影响

目的 :研究甘草酸二铵 (diammoniumglycyrrhizinate ,DG)对小鼠和家兔外周血清胆碱酯酶的影响。 方法 :昆明种小鼠尾静脉注射甘草酸二铵 10～ 2 0mg·kg-1,家兔耳缘静脉注射甘草酸二铵 10～ 2 0mg·kg-1,静脉注射 30min后 ,采血测定血清胆碱酯酶活性。结果 :应用甘草酸二铵组的小鼠、家兔胆碱酯酶活性明显低于生理盐水组 ,但高于敌百虫组。结论 :甘草酸二铵可抑制血清胆碱酯酶活性 ,但抑制作用低于敌百虫组。     

18α-甘草酸固体脂质纳米粒抗大鼠急性肝损伤作用研究

目的 研究18α-甘草酸固体脂质纳米粒（18α-glycyrrhizic acid solid lipid nanoparticles,18α-GL-SLN）的抗大鼠急性肝损伤作用。方法 用CCl4致大鼠急性肝损伤,以生化指标和病理变化评价18α-GL-SLN的抗肝损伤作用。结果 与模型组比较,18α-GL-SLN各剂量组和18α-GL组ALT、AST、TBil、γ-GT、ALP水平明显降低,差异有统计学意义（P〈0.05）,提示对大鼠急性肝损伤均有一定的治疗作用,尤其是18α-GL-SLN中、高剂量组,效果优于18α-GL组（P〈0.05）;病理切片显示各给药组肝组织损伤明显减轻。结论 18α-GL-SLN有抗CCl4致大鼠急性肝损伤作用,并且其作用优于18α-GL。     

甘草酸差向异构体在大鼠体内的药动学研究

目的研究甘草酸的差向异构体在大鼠体内的药物动力学特征。方法大鼠按25mg.kg-1的剂量分别灌胃给予甘草酸2种差向异构体,使用HPLC测定血药浓度,以DAS2.0软件拟合药动学参数,并用SPSS统计软件对α-甘草酸组和β-甘草酸组的药动学参数进行比较。结果甘草酸的差向异构体在体内转化为甘草次酸后主要药动学参数分别为：α-甘草酸组AUC0-36为（57.04±14.64）μg.mL-1.h,Cmax为（4.68±2.56）μg.mL-1t1/2为（5.56±1.65）h,tmax为（10.0±4.0）h;β-甘草酸组AUC0-36为（36.55±13.18）μg.mL-1.h,Cmax为（4.24±1.69）μg.mL-1,t1/2为（7.88±2.40）h,tmax为（9.0±1.1）h。结论甘草酸的差向异构体在体内转化为甘草次酸后的主要药动学参数存在显著性差异。     

A comparison of the distribution of two glycyrrhizic acid epimers in rat tissues.

The distribution characteristics of two glycyrrhizic acid (GL) epimers, i.e. alpha-GL and beta-GL in rat tissues were examined. At 5, 15, 30, 60, and 180 min after i.v. administration of a single alpha-GL or beta-GL injection (21.0 mg/kg) in rats, the concentrations of these epimers in rat tissues were determined by reverse phase-high performance liquid chromatography (RP-HPLC) using the internal standard method. Alpha-GL and beta-GL were both rapidly distributed in the tissues. The concentrations of alpha-GL in the liver were significantly higher than those of beta-GL, but were lower than or similar to those of beta-GL in the other tissues. The concentrations of alpha-GL in all the tissues declined rapidly, and were lower than or similar to the detection limit for quantification at 180 min after i.v. administration. However, beta-GL concentrations remained rather high in the tissues, and maintained 10-50% of their peak value. According to these results, distinct differences were found in the distribution and metabolism in the rat tissues after i.v. administration of the two GL epimers, with these differences being closely related to the different configuration of alpha-GL and beta-GL.     

Pharmacokinetics of α-dihydroergocriptine in rats after single intravenous and single and repeated oral administrations

The pharmacokinetics of α-dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged α-dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg^?1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half-life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg^?1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half-life of 0.02 h, a distribution half-life of 2.15 h and an elimination half-life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs. Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first-pass effect).     

The pharmacokinetics and metabolism of idazoxan in the rat

1. [2'-14C]Idazoxan was rapidly and completely absorbed after its oral administration to rats. 2. After administration of either [2'-14C] or [6,7-3H]idazoxan, radioactivity was taken up by a wide range of tissues and became localized, especially in the organs of metabolism and excretion. Quantitative distribution patterns were route-dependent such that oral dosing resulted in lower radioactivity concentrations in all tissues apart from liver. 3. Clearance of idazoxan (94-144 ml/min per kg) was due mostly to metabolism and was independent of dose. Oral bioavailability in male rats at low oral doses of idazoxan (10 mg/kg) was about 1%, but increased with increasing dose to 23% at 100 mg/kg. Oral bioavailability in female rats was considerably higher than in male rats, at all doses studied. Brain idazoxan levels were in equilibrium with those in plasma, but ten-fold higher. 4. Elimination of radioactivity after administration of 14C-idazoxan was via the urine and the faeces (about 75% and 20% of dose respectively) and occurred essentially in the 24 h period immediately after dosing. By 96 h after dosing, elimination was virtually complete, with less than 0.5% dose remaining in the carcasses. 5. Biotransformation was by hydroxylation at positions 6 and 7 to form phenolic metabolites, which were excreted as glucuronide and sulphate metabolites in urine, but unconjugated in faeces. Other minor metabolic routes were 5-hydroxylation or oxidative degradation of the imidazoline ring, but these pathways were of quantitatively minor importance in the rat.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 2nd communication: whole-body autoradiographic distribution of [3H]-enprostil in rats

The distribution of radioactivity was studied by whole-body autoradiography in rats after oral or intravenous administration of [3H]-enprostil ((+/-)-11a-15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorp r osta-4,5,13(t)- trienoic acid methyl ester, TA-84135) at a dose of 23 micrograms/kg. After oral administration to male rats, radioactivity in almost all the tissues and organs reached a peak within 15 min to 1 h. The highest levels of radioactivity were found in the contents of the stomach and intestine. High levels of radioactivity were also observed in the liver and kidney, and moderate levels were found in the lung, blood, dental pulp and the walls of the stomach. Radioactivity was the lowest in the skeletal muscle, testis, eye and brain. After reaching peak levels, radioactivity in the body decreased gradually, and it was detected only in the excretory organs at 24 h after drug administration. The distribution pattern after the intravenous dose was essentially similar to that after oral administration. The distribution profile of radioactivity in non-pregnant female rats after an oral dose was similar to that in male rats. Placental transfer and excretion in milk of radioactivity was slight. When the affinity of this compound to the melanin-containing tissues such as the uveal tract of the eye and the hair follicle was examined using pigmented rats, no tendency to retention of radioactivity in these tissues was observed.     

Comparative study on the distribution of α- and γ-hexachlorocyclohexane in the rat with particular reference to the problem of isomerization

1. Blood levels and tissue distributions of α-, β-, γ- and δ-hexachlorocyclohexane (HCH) were studied following oral administration of α-HCH and γ-HCH to rats.

2. Following administration of α-HCH, there was no evidence of β-HCH, γ-HCH or δ-HCH, nor could transformation into α-HCH, β-HCH or δ-HCH be detected after exposure to γ-HCH.

3. After eight weeks of administration, tissue retention of α-HCH was 10–20 times greater than that of γ-HCH.

4. γ-HCH was eliminated to a much greater extent than α-HCH from the tissues, and in particular from fatty tissue.

5. α-HCH accumulated in fat and brain, while γ-HCH showed very low affinity for lipid.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 1st communication: absorption, distribution and excretion in the mouse, rat and rabbit

Absorption, distribution and excretion of [3H]-enprostil ((+-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorpr osta -4,5,13(t)-trienoic acid methyl ester, TA-84135), a new anti-ulcer prostaglandin, were studied in mice, rats and rabbits. Radioactivity associated with enprostil was rapidly absorbed from the gastrointestinal tract with Tmax values of 15 or 30 min. Absorption was also efficient inasmuch as approximately 80% of an oral dose was recovered in bile and urine in 24 h in bile duct-cannulated rats. Experiments in pylorus-ligated, bile duct-cannulated rats demonstrated that enprostil was mainly absorbed from the intestine, rather than from the stomach. In mice given oral doses of 2, 8 and 32 micrograms/kg, Cmax and AUC values of enprostil radioequivalents increased proportionately to the increase in dose, indicating linear kinetics over this dose range. Distribution of enprostil-associated radioactivity was investigated in rats by quantitating tritium in various tissues after the oral administration of [3H]-enprostil. Radioactivity in tissues was highest at 15 or 30 min after dosing. Highest levels of radioactivity were found in the stomach and intestines, the organs which came into direct contact with the dose, and the liver and kidney, the organs involved in excretion of enprostil. The rate of elimination of enprostil-associated radioactivity from all tissues and from plasma was similar. Enprostil-associated radioactivity did not accumulate in any tissue. Radioactivity was found in fetuses following oral administration of [3H]-enprostil to rats on the 12th or 19th day of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

长期服用氨酰心安对大鼠心脏肾上腺素受体的影响

目的：了解心脏病患者长期服用β－受体桔抗剂后,心功能究竟能否得到改善。方法：给大鼠服用选择性β１－受体桔抗剂氨酰心安１２ｗｋ后,采用放射配体结合实验和离体左心房收缩功能实验,观察大鼠心脏β－受体及其亚型和α１－受体的数量、分布以及左心房收缩功能的改变。结果：长期服用氨酰心安后心脏α１－受体、总β－受体的密度和β１－受体、β２－受体亚型所占β－受体总数的比例均无明显改变。但氨酰心安组左心房异丙肾上腺素的浓度－收缩效应曲线较对照组明显左移。氨酰心安组的选择性β１－受体桔抗剂 ＣＧＰ２０７１２Ａ桔抗异丙肾上腺素介导的正性变力效应的 ＰＡ２值显著大于对照组;而 ＩＣＩ １１８５５１桔抗异丙肾上腺素的ＰＫＢ值在两组间无显著性差异。用高效液相色谱法测定氨酰心安组血浆氨酰心安浓度为３．５ｕｍｏｌ／Ｌ,血浆中去甲肾上腺素水平两组间无显著性区别,但氨酰心安组血浆肾上腺素水平明显低于对照组。结论：长期服用β１－受体桔抗剂后,心脏β－受体对激动剂异丙肾上腺素的敏感性明显增强,且以β１－受体的敏感性增强更为显著。但β－受体及其亚型的受体数目并无明显改变。此外,长期服用β１－受体桔抗剂后,服用氨酰心安组大鼠的血浆肾上腺素水平明显低于对照?     

Might adriamycinol contribute to adriamycin-induced cardiotoxicity?

The pharmacokinetics of adriamycin (ADR) and its 13-hydroxylated-metabolite adriamycinol (ADR-ol) was investigated during treatment with ADR in rats at a dose of 2 mg/kg i.v., once a week for 3 weeks. At various times, samples of blood and cardiac and pulmonary tissues were collected to measure the amount of ADR and ADR-ol by an HPLC procedure. Periodical ECG monitoring was performed during the study; the severity of cardiac lesions was histologically evaluated at the end of treatment. During the first 180 min after ADR administration, plasma levels of ADR and ADR-ol rapidly decreased; ADR levels in cardiac and in pulmonary tissues increased between the 15th and 30th min and than decreased between the 60th and 180th min; on the contrary, ADR-ol was undetectable in either cardiac or pulmonary tissues during the first 3 hours following ADR administration. Between the 1st and 3rd weeks of treatment, plasmatic levels of ADR and ADR-ol were unchanged; in a similar way, both cardiac and pulmonary tissue levels of ADR were constant during the period of treatment. By contrast, the cardiac tissue level of ADR-ol significantly increased between the 2nd and 3rd weeks. ECG tracings showed maximal enlargement of both QRS and S alpha T at the end of the 3rd week. The histological examination of cardiac tissue indicated the occurrence of degenerative changes in 20% of rats at the end of the experiment. Overall results seem to indicate that ADR-ol is produced and stored in cardiac tissue during repeated ADR administration; as a consequence the cytotoxic metabolite might contribute to the cardiotoxic effect of ADR.