7-(4-氯苄基)-7,8,13,13a-四氢小檗碱在家兔体内的代谢产物分析

7(4氯苄基)7,8,13,13ａ四氢小檗碱(ＣＴＨＢ)结构式为:是中国药科大学对小檗碱进行结构改造得到的新化合物,有较强的抗心律失常作用,已在多个国家申请了专利。我们曾对该化合物进行了Ｃ,Ｈ化学位移的全归属[1],鉴定了在大鼠体内的主要代谢产物[2]。为了比较该化合物在不同动物体内的代谢情况,我们用家兔进行试验,前文[3]已经报道了用ＨＰＬＣ/ＤＡＤ对家兔胆汁中7(4氯苄基)7,8,13,13ａ四氢小檗碱代谢产物的鉴别,本文进一步研究该化合物在家兔体内的代谢途径。材料与方法　　动物　家兔,重25ｋｇ,由本校动物房提供。　　仪器　ＨＰ1100ＨＰＬ…     

呋喃丙胺体内代谢的研究

本文利用比色法测定了家兔门静脉血液及心脏血内呋喃丙胺(F30066)的含量.应用光谱分析,纸层析及柱层析法研究了宿主肠道内及尿内呋喃丙胺代谢产物.采用实验治疗血吸虫病的方法,比较胃肠道外不同给药途径的治疗效果.家兔口服呋喃丙胺经胃肠道吸收后,在门静脉血液内有一定浓度的药物.此药经过肝脏转化后部分排泄入肠道.此肠内转化物无治疗血吸虫病的效用.口服呋喃丙胺后尿内可发现二个药物的代谢产物.经体内、体外试验此二代谢产物,均无杀死血吸虫的作用.静脉、肌肉注射呋喃丙胺混悬液治疗血吸虫病家兔都无疗效.腹腔注射呋喃丙胺治疗小白鼠血吸虫病却获得良好效果.     

呋喃丙胺体内代谢的研究

本文利用比色法测定了家兔门静脉血液及心脏血内呋喃丙胺(F30066)的含量.应用光谱分析,纸层析及柱层析法研究了宿主肠道内及尿内呋喃丙胺代谢产物.采用实验治疗血吸虫病的方法,比较胃肠道外不同给药途径的治疗效果.家兔口服呋喃丙胺经胃肠道吸收后,在门静脉血液内有一定浓度的药物.此药经过肝脏转化后部分排泄入肠道.此肠内转化物无治疗血吸虫病的效用.口服呋喃丙胺后尿内可发现二个药物的代谢产物.经体内、体外试验此二代谢产物,均无杀死血吸虫的作用.静脉、肌肉注射呋喃丙胺混悬液治疗血吸虫病家兔都无疗效.腹腔注射呋喃丙胺治疗小白鼠血吸虫病却获得良好效果.     

黄山药总皂苷肠内菌代谢及代谢产物吸收的研究

目的 :本文离体和整体观察人和大鼠肠内菌对黄山药总皂苷(DX)的代谢作用及整体给予DX后吸收入血的有效成分。方法 :用薄层色谱(TLC)及电喷雾质谱(ESI -MS)法检测粪中DX及其代谢产物。整体给予大鼠灌服DX900mg/kg ,于给药后不同时间采集尿及血清样品 ,用ESI -MS检测吸收入血成分。结果 :DX容易被人和大鼠消化道菌群代谢 ,随着代谢时间的延长 ,出现了各种甾体皂苷的降解产物及终产物薯蓣皂苷元 (Dio)。整体实验表明 ,在大鼠血及尿中均发现分子量为415 3的代谢产物 ,经ESI -MS二级质谱分析 ,上述分子量的化合物为Dio。结论 :DX可被人和大鼠肠内菌代谢 ,DX经口服后Dio被吸收入血。     

地尔硫和它的代谢产物在人血样品中的稳定性

地尔硫(diltiazem,以下简写为Dil)是一种钙通道阻滞剂,被广泛用于治疗各种心绞痛、高血压和窦性心动过速。Dil可经脱乙酰作用、N-脱甲基作用、O-脱甲基作用和结合作用等广泛代谢。有人报告,口服Dil后,血浆中主要代谢物为脱乙酰基Dil(M_1),最近也有人报告N-脱甲基Dil(MA)可能是血浆中占优势的代谢物。作者用HPLC法研究长期用Dil治疗的病人血样中Dil及其代谢物的稳定性,发现病人血中50％母体药转化为MA,只有12％转化为M_(1)。当全血在采样和离心之间于室温放     

人参皂苷Rg1在大鼠体内的代谢与排泄研究

目的 考察静注和口服给予大鼠人参皂苷Rg1溶液后的体内代谢与排泄情况.方法 以Wistar大鼠为模型动物,分别iv和ig给予一定量的人参皂苷Rg1溶液,然后按时收集其排泄物(尿液与粪便),预处理后用HPLC检测.结果 iv给予大鼠人参皂苷Rg1溶液后,有47.46%的原型药和代谢产物通过粪便排出体外;而51.31%的药物以原型或代谢产物的形式通过尿液排出体外;ig给予大鼠人参皂苷Rg1溶液后,绝大部分Rg1都被代谢,排泄物中仅有9.04%的原型药物,且仅有13.6%的人参皂苷Rg1被吸收进入人体再通过尿液排出,还有82.82%的原型药物和代谢产物直接通过粪便排出.结论 人参皂苷Rg1在胆汁中排泄明显,其口服吸收差,生物利用度低,且极易被代谢.     

基于超高效液相色谱 -质谱联用技术的慢性肾脏病骨代谢异常大鼠血清代谢组学研究

目的通过超高效液相色谱 -质谱( UHPLC-MS)联用技术探索慢性肾脏病骨代谢异常( CKD-BD)大鼠血清代谢组学变化。方法该研究于 2021年 1月至 2022年 4月进行,选择 16只 8周龄 SPF级 SD雄性大鼠经过 1周适应性喂养后,采用随机数字表法分为两组,每组 8只。健康对照( NC)组:使用普通大鼠饲料喂养 90 d;CKD-BD组:采用高磷高腺嘌呤饲料喂养 60 d之后更换高磷饲料喂养 30 d后处死,并通过生化检测及骨形态计量学方法对模型进行验证。造模成功后通过 UHPLC-MS比较 CKD-BD组大鼠与 NC组大鼠血清代谢产物变化,通过多元统计分析等方法鉴定两组间差异代谢物,并通过生物信息学方法对差异代谢产物进行功能注释。结果与 NC组大鼠相比, CKD-BD组大鼠血肌酐、血磷显著升高,血钙显著降低( P<0.01)。骨形态计量学检测 NC组大鼠骨矿化沉积率( MAR)为( 1.90±0.61)μm/d,CKD-BD组大鼠 MAR为( 2.80±0.73)μm/d,差异有统计学意义( P<0.05)。 NC组大鼠骨形成率 /骨体积( BFR/BV)为( 0.41±0.20)%/d,CKD-BD组大鼠 BFR/BV为( 1.25±0.41)%/d,差异有统计学意义( P<0.05)。代谢组学检测结果提示,与 NC组相比, CKD-BD组糖基磷脂酰肌醇锚定蛋白合成等通路上调。自噬、胆汁酸合成分泌、胆固醇代谢、牛磺酸和次级牛磺酸代谢、甘油磷脂代谢等通路下调( P<0.05)。结论通过 UHPLC-MS技术比较 CKD-BD大鼠与正常大鼠血清代谢产物,发现 CKD疾病状态下血清代谢产物发生变化, CKD-BD组糖基磷脂酰肌醇锚定蛋白合成通路上调,与自噬相关的代谢通路下调,这些可能参与了 CKD-BD发生。     

液相色谱-串联质谱法分析抗肿瘤新药乙烷硒啉在大鼠体内的代谢产物

本研究对抗肿瘤新药1,2-[二(1,2-苯并异硒唑-3(2H)-酮)]乙烷(乙烷硒啉,BBSKE)在大鼠体内的代谢产物进行鉴定。在灌胃给予大鼠单剂量乙烷硒啉200mg·kg-1后,采用液相色谱-串联质谱法(LC-MSn)对大鼠尿液、粪样、胆汁和血浆中的代谢产物进行检测,通过全扫描和选择离子扫描,以及根据多级质谱裂解规律对代谢物的结构进行分析。研究发现在大鼠尿样、粪样、胆汁和血浆中检测到3种Ⅰ相代谢产物和1种Ⅱ相代谢产物,其代谢途径分别为氧化、甲基化、硫甲基化和葡萄糖醛酸化反应,提示乙烷硒啉在大鼠体内的代谢方式可能是通过氧化、甲基化及葡萄糖醛酸化反应形成代谢产物。     

左旋四氢巴马汀对大鼠甲基苯丙胺辨别行为的影响

研究左旋四氢巴马汀 (l-THP)对药物精神依赖性的影响。方法··:用固定比率食物强化方法使大鼠对甲基苯丙胺 (MA)形成稳定的辨别效应。以多巴胺受体拮抗剂Sch -23390和螺哌隆拮抗MA效应 ,观察辨别效应的变化 ;以l-THP替代及对抗MA效应 ,并观察其对大鼠MA辨别行为重建的影响。结果·· :大鼠对MA形成稳定的辨别 ;0.001mg·kg-1Sch -23390及0.01mg·kg-1螺哌隆均拮抗训练剂量MA的辨别效应 ;5mg.kg-1l-THP不能替代训练剂量MA ,但能阻断其辨别效应 ;l-THP明显降低大鼠MA辨别行为重建时的踏杆正确率 (P<0.05)。结论·· :MA可使大鼠形成稳定的辨别效应 ,而且DA受体参与调控MA的这种效应 ;l-THP能阻断MA辨别行为 ,影响MA辨别行为的重建 ,表明其可降低MA精神依赖性的形成。     

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％     

Phenobarbitone interaction with oral contraceptive steroids in the rabbit and rat.

1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls. 4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.     

Species comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits, and rats

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and related heart diseases. It is extensively metabolized into a host of metabolites, some of which have potent pharmacological activities. In this study, the pharmacokinetics and metabolism of DTZ was investigated in humans, dogs, rabbits, and rats after each species (n = 4 or 5) was given a single oral dose of DTZ. After the drug administration, blood and urine samples were collected for 12 and 48 hrs, respectively. DTZ and six of its metabolites were quantitated in our laboratory by HPLC. The results indicated that, in humans, the major metabolites in plasma were N-monodesmethyl diltiazem (MA), deacetyl diltiazem (M1), and deacetyl N-monodesmethyl diltiazem (M2). These metabolites were also detected in the plasma of dogs, rabbits, and rats. However, there were quantitative differences. For example, in the humans and dogs, MA was the most abundant metabolite in plasma, while M1 and M2 were most prominent in the rabbits and rats, respectively, and M2 was a relatively minor metabolite in dog plasma. Less than 5% of the dose was recovered as unchanged DTZ in the urine of all the tested species. The most abundant metabolites in urine appeared to be MA and deacetyl N,O-didesmethyl diltiazem, although there were considerable inter- and intra-species variations. Two additional metabolites were detected in the urine of the humans, dogs, and rabbits, but not in the rats. They were tentatively identified as O-desmethyl diltiazem and N-O-didesmethyl diltiazem, using electron impact and ammonia chemical ionization mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and metabolism of radiolabelled pentachloroanisole in rats and rabbits

Male Sprague-Dawley rats and New Zealand White rabbits were administered ¹⁴C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after administration of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the administered radiolabel in the urine and 32.4% in the faeces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faeces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH). 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; faecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolite(s) (10%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH. 8% to free PCP and 34% to conjugated PCP. Faecal metabolites consisted of PCP and conjugated material.     

Hemodynamic effects of synephrine treatment in portal hypertensive rats

Synephrine, a sympathomimetic alpha1-adrenoceptor agonist, has been shown to induce dose-dependent portal hypotensive effects after acute intravenous infusion. The present study was undertaken to investigate the hemodynamic effects of 8-day administration of synephrine in portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL) or bile duct ligation (BDL). Portal hypertensive rats were allocated into one of two groups: vehicle group (0.1 N HCl, 0.5 ml/12 h) or synephrine group (1 mg/kg per 12 h), with 7 rats in each group. Synephrine or vehicle was administered by gavage into PVL and BDL rats for 8 consecutive days. Systemic as well as splanchnic hemodynamic parameters were measured thereafter. Synephrine significantly ameliorated the hyperdynamic state in both PVL and BDL rats. The portal venous pressure in PVL and BDL rats (-13.5% and -10.1%, respectively), portal tributary blood flow (-19.5% and -20.4%) and cardiac index (-12.1% and -18.8%) were significantly reduced, while mean arterial pressure (10.4% and 23.4%) and systemic (26.3% and 51.0%) as well as portal territory (47.1% and 67.7%) vascular resistance were enhanced by treatment of synephrine as compared with vehicle treatment. Our results showed that eight-day administration of synephrine exerted beneficial hemodynamic effects in two models of portal hypertensive rats.     

间硝苯啶、硝苯啶与尼群的平对动物降压作用的比较性研究

在清醒正常血压大鼠、免以及肾型高血压大鼠,比较了m-nif、nif及nitr的降压强度,和降压的时间动态过程,三药的降压作用与对照组及自身前后对比,统计学上均非常显著。m-nif与nitr降压持续时间较nif长。从清醒正常血压大鼠降压的量效关系比较,m-nif、nif和nitr的ED₅₀)分别为33.7±3.4,45.6±3.6和51.2±4.1 mg/kg(即90±9,132±10,142±11μmol/kg)。按克分子量计算对比m-nif的降压强度最大,nitr最弱。但三药对正常血压及肾型高血压动物的降压作用,按组间对比,无统计学差异。     

甲胺及其代谢产物甲醛在动物体内的药代动力学

目的进一步了解血浆氨基脲敏感型胺氧化酶(SSAO)活性与内源性甲醛的生理学与病理学意义。方法采用高效液相色谱法测定小鼠、大鼠和兔血浆中SSAO活性和静脉给予甲胺后甲胺及其代谢产物甲醛浓度。结果小鼠、大鼠和兔血浆中SSAO活性分别为(4.1±1.0),(2.0±0.3)和(325.8±3.9)μmol·h-1·L-1。3种动物单次iv甲胺后,甲胺的分布和代谢迅速。小鼠单次iv4.2mg·kg-1甲胺后甲醛浓度在代谢初期缓慢上升,在20~40min达峰后缓慢消除。而大鼠单次iv4.2mg·kg-1甲胺后血浆甲醛浓度无明显改变。兔单次iv2.3,9.6和36.8mg·kg-1甲胺后,甲胺AUC与剂量不成比例,Cl随剂量增加明显减少,呈非线性动力学特征。甲醛在兔体内消除较快,甲醛AUC与甲胺剂量的比值和全身清除率Cl无明显差异,但ke随给予甲胺剂量的增大而减少,t1/2显著延长。结论甲胺在3种动物间代谢情况相似,其代谢产物甲醛则明显不同。甲胺给予剂量的不同可能导致甲胺代谢动力学的改变,进而可能影响甲醛的代谢。     

The absorption and metabolism of methyl cinnamate

Analysis of the gut contents of rats killed at intervals after dosage with methyl cinnamate or cinnamic acid suggested that both ester and acid were rapidly absorbed; at no time was more than 5% of the dose detected in the lower part of the gut. Not more than 9% of the administered methyl cinnamate was detected in the stomach as cinnamic acid whereas at least 40% of the small amounts of the dosed ester detected in the lower part of the gut was present as cinnamic acid. No ester was detected in the peripheral blood of dosed rabbits or rats and only traces were detected in portal and heart blood samples taken from dosed rats. Cinnamic acid and methanol were readily detected in the blood of rabbits and rats which had been dosed with methyl cinnamate. No qualitative or significant quantitative difference was detected in the metabolism of the ester as compared with the parent acid. In addition to the metabolites of cinnamic described in the literature p-hydroxyhippuric acid was excreted as a minor metabolite of both cinnamic acid and methyl cinnamate.     

Absorption and disposition of epithiosteroids in rats (2): Avoidance of first-pass metabolism of mepitiostane by lymphatic absorption

1. Absorption of mepitiostane (MP) from the gastrointestinal tract was examined using thoracic duct-cannulated rats.

2. When ¹⁴C-MP was administered into the small intestine, 34% of the radioactivity was recovered in the 6-h thoracic duct lymph. More than 90% of this radioactivity was due to unchanged MP and most of the MP in the lymph was carried in the lipid core of the chylomicrons and VLDL.

3. Radioactivity in the portal blood was extensively extracted by the liver and excreted into bile as polar metabolites. Thus, most unchanged MP which entered the systemic circulation following oral administration was drug absorbed via the intestinal lymphatics.

4. MP avoids the first-pass effect by lymphatic adsorption.     

扁桃酸在大鼠、小鼠和兔组织中的立体选择性代谢(英文)

目的研究扁桃酸(MA)在大鼠、小鼠和兔组织中的立体选择性代谢,探讨MA代谢酶存在的部位、辅酶依赖性等性质以及可能的种属差异。方法MA对映体与大鼠、小鼠和兔的肝脏、肺、肾脏S9和微粒体共孵育,HPLC检测代谢并用柱前衍生化方法进行手性分析。同时考察辅酶NADH和NADPH及醇脱氢酶竞争性底物乙醇和抑制剂4-甲基吡唑对S-MA代谢的影响。结果S-MA在大鼠肝和肾S9中被代谢为PGA,而R-MA无代谢。两对映体在小鼠和兔组织中均不被代谢。乙醇和4-甲基吡唑不影响酶的活性,该代谢顺利进行的重要辅酶是NADPH而非NADH。结论大鼠中参与MA立体选择性代谢的酶是存在于胞浆或线粒体中的具有NADPH依赖性的非微粒体酶,而不是醇脱氢酶。MA的立体选择性代谢存在种属差异性。     

A recirculatory model for local absorption and disposition of ciprofloxacin by measuring portal and systemic blood concentration difference.

A recirculatory model for the portal-systemic blood concentration difference (P-S difference) was developed to separately evaluate the rate and extent of absorption from the gastrointestinal tract into the portal system and disposition of a drug in the body. To apply this model to pharmacokinetic analysis, ciprofloxacin was selected as a model drug possessing a moderate intestinal absorption, and renal and hepatic elimination. The portal and systemic blood samples were simultaneously taken from rats at appropriate time points after intravenous and oral administration of ciprofloxacin at a dose of 5 mg/kg. After intravenous administration, little or no difference in the concentrations between the portal and systemic blood was observed, whereas after oral administration the concentrations of ciprofloxacin in the portal blood were consistently higher than those in the systemic blood over the time studied. This difference observed after oral administration is attributed to the absorption of ciprofloxacin from the gastrointestinal tract into the portal system. On the basis of the moment analysis deduced from the recirculatory model, the portal blood flow rate (Q(p)), the local absorption ratio from the gastrointestinal tract into the portal system (F(a)), the hepatic recovery ratio (F(h)), and bioavailability (BA) were then estimated. The obtained Q(p) of 2.81 L/h/kg, F(a) of 32.6, F(h) of 68.1, and BA of 22.2% were found to be in good agreement with the reported values. Furthermore, the mean local absorption time from the gastrointestinal tract into the portal system (t(a)) calculated by a nonlinear least-squares program [MULTI (FILT)] was almost identical with that by the global moments. These results suggest that the model proposed in this study would be useful for evaluating both in vivo absorption and disposition of drugs.