蒿苯酯在大鼠的药物代谢动力学

大鼠ig蒿苯酯后吸收迅速,其药时曲线出现双峰现象。SPLI非房室模型统计矩计算结果表明,3剂量组平均驻留时间MRT约在12h,半衰期T_1/2约在8h,基本一致。将前8h第一峰血药浓度曲线用3P87程序拟合,药代动力学模型为一室模型。大鼠ig蒿苯酯后2h药物可广泛分布于各组织,6h后各组织中药物浓度均很低。ig蒿苯酯后主要经尿排出,48h经粪尿累积排出70.4%。蒿苯酯平均血浆蛋白结合率约为70%。提取物形式的鉴别结果表明,大鼠ig蒿苯酯后血中以蒿苯酯原型药为主,尿中蒿苯酯及还原青蒿素均有,粪中则以还原青蒿素为主。     

奥拉西坦在大鼠和小鼠的药代动力学研究

目的： 研究奥拉西坦(ORC)在大鼠和小鼠的药代动力学。方法： 采用HPLC法测定生物样品中ORC浓度, 在大鼠和小鼠进行其药代动力学、吸收、分布、排泄试验。结果： 大鼠灌胃给ORC 100,200和400 mg.kg^-1后表明, 本品po吸收速率快,达峰时间短,药物自血清消除较快。小鼠1次ig给药100 mg.kg^-1后,80%以上药物在给药后3 h内由消化道消失;药物吸收后能分布到各种组织脏器, 给药后36 h累计尿排泄原形药物量约为药物剂量的80%; 蛋白结合率低,平均结合率为10.5%。结论： 奥拉西坦是一吸收快、消除快、主要以原形药物由尿排泄、蛋白结合率低的药物。     

重组肿瘤坏死因子在小鼠体内的分布和代谢

用^125I标记重组的肿瘤坏死因子（rTNFα），作小鼠体内示踪实验，观察其体内分布、代谢和排泄过程。小鼠药代动力学研究结果表明，iv后消除上半衰期约7h，AUC与剂量呈线性关系。im后生物利用度为29％，峰浓度出现于给药后2h。分布实验测定iv后各时间每克湿组织中所含rTNF α的浓度，在给药后，骨髓中浓度与血浆中相等且并行下降，脾、肺、肾中的浓度与血液各相近，0．5h前以肝内浓度最高，但胃中浓度在给药后2－8h 达高峰，为血浆中浓度的5倍，远高于其它组织，小肠中浓度也随后略有升高，但低于胃，高于其它组织。 血浆电泳发现有2个主要放射峰，一为原形药物，另一为分子量较大的代谢产物。该代谢物占的比例在15min时为29％，到4h升至63％，而原形药物从15min时的39％降至23％。血中低分子代谢产物很少，但在尿样中75％以上为低分子量代谢产物。小鼠静注rTNFα后，24h尿粪总排出为给药剂量的87％。     

高效液相色谱法测定大鼠组织及血浆中9-硝基喜树碱含量高效液相色谱法测定大鼠组织及血浆中9-硝基喜树碱含量

目的 建立高效液相色谱法测定大鼠血浆及组织样品中9-硝基喜树碱,并研究其在大鼠体内的分布特点。方法 血浆及组织样品经液-液萃取后,分别以乙腈-水-甲酸(35∶65∶2)或乙腈-水-甲酸(30∶70∶2)为流动相,使用Hypersil BDS C₁₈色谱柱进行分离,检测波长为UV 370 nm。结果该法测定9-硝基喜树碱在血浆中线性范围为25～1 600 μg·L^-1。药物iv后在大鼠体内广泛分布,肺中浓度最高,并在肺和肝中有蓄积现象。ig给药后,药物在胃中浓度最高,肠组织次之,大多数组织中药物浓度较低。结论该法操作简便、快速,适用于9-硝基喜树碱临床前药代动力学研究。     

萘哌地尔在大鼠体内的药代动力学

为全面了解萘哌地尔(Naf)在大鼠体内的代谢过程,用反相HPLC-UV法,给大鼠ig10,20,30mg·kg^-1Naf后,测定在不同时间各组织和体液中Naf的含量。结果表明,Naf在大鼠体内药代动力学为二室模型,T_1/2α为0.47～1.01h,T_1/2β为4.78～7.08h,达峰时间T(peak)为0.42～0.90h,Cmax,AUC随剂量升高而增大。给药后15min,肠壁组织浓度最高,其次为肝、肺;2h以后,除睾丸、卵巢和子宫外,其余组织药物浓度逐渐降低。尿、粪及胆汁中原形药总排出量不足给药量的1%,提示Naf在大鼠体内有首过效应及代谢物生成。在100～500mg·ml^-1浓度范围内,Naf血浆蛋白结合率为82%～97%。     

葛根有效成分的代谢研究——Ⅲ.葛根素的代谢及其药代动力学分析

本文建立了一个用薄层及紫外光分光光度法分离并测定生物样品中葛根素的方法,并用该法研究了葛根素在大鼠体内的代谢,分析了其药代动力学特点,并观察了口服后在人体的排泄情况。大鼠静脉注射后药物在肾脏含量较高,血浆、肝、脾次之,药物可通过血脑屏障进入脑组织,但脑中含量较低。血浆药-时曲线分快、慢两个时期。根据开放形二室模型数学公式计算葛根素各药代动力学参数为:t_1/2(α)=3.0分,t_1/2(β)=18.0分,V₁=19.9 ml,V₂=33.7ml,V_d=53.7ml,α=0.23/分,β=0.04/分,K₁₂=0.08/分,K₂₁=0.09/分,K₀=0.10/分,清除率=2.0 ml/分。此结果表明葛根素在体内分布广、消除快、不易积畜。体外实验证明,葛根素可被大鼠血及肝、肾等组织所代谢,且可与肝、肾、肺及血浆蛋白相结合,其与血浆蛋白的结合率达24.6%。大鼠灌胃葛根素后药物吸收较快,但吸收程度较差,灌胃后24小时自粪及胃肠道内容物回收的药物为剂量的37.3%。体外实验证明,葛根素在胃肠道内破坏很少。大鼠灌胃葛根素后24小时自尿及粪分别排出1.85%及35.70%,静脉注射后分别自尿、粪及胆汁排出剂量的37.62%,7.39%及3.65%。正常成人口服葛根素后36小时仅有0.78%自尿排出,72小时自粪排出剂量的73.3%。本文对葛根素及黄豆甙元的代谢特点进行了讨论。     

染料木黄酮在Beagle犬体内的药代动力学染料木黄酮在Beagle犬体内的药代动力学

目的研究染料木黄酮(genistein)在Beagle犬体内的药代动力学。方法染料木黄酮ig后用反相高效液相色谱法测定犬血浆、尿及粪便中原型药物浓度,血浆药物浓度-时间数据用3P97药代动力学软件分析。结果Genistein在Beagle犬体内的代谢符合一室模型,ig后0.29 h达药峰浓度,t1/2 Ke为0.52 h。给药后24 h内有10.79%的原型药物由尿排出,21.55%的原型药物由粪便排出。60 h内有13.00%的原型药物由尿排出,有52.46%的原型药物由粪便排出。结论Beagle犬ig染料木黄酮后吸收迅速,血浆中药物的消除速度快,药物主要以原型经尿和粪便排出体外。     

槐定碱纳米脂质体在大鼠体内药代动力学及组织分布研究

目的:研究槐定碱纳米脂质体静脉给药后在大鼠体内药代动力学及组织分布。方法:大鼠尾静脉注射给药后,采用HPLC法测定血浆药物浓度,比较盐酸槐定碱注射液、槐定碱纳米脂质体的药代动力学;另HPLC法测定各组大鼠心脏、肝、脾、肺、肾中4 h内的槐定碱浓度,分析药物组织分布情况。结果:槐定碱纳米脂质体的大鼠药时曲线AUC是普通注射液的2.42倍,体内滞留时间延长;各组织中槐定碱浓度均在0.5 h达最高后开始降低;与槐定碱注射液比较,静脉注射槐定碱纳米脂质体后4 h内的平均浓度在肝、脾中均升高,在其他组织中的浓度均降低。结论:槐定碱纳米脂质体能提高药物在肝、脾中的分布,具有肝、脾靶向性,尤其是肝靶向性。     

13-甲基豆蔻酸在大鼠体内的药代动力学研究

目的　研究 1 3 -甲基豆蔻酸在大鼠体内的药代动力学。方法　用毛细管柱气相色谱法测定生物样品中的原形药物浓度 ,在大鼠体内进行血浆药代动力学、分布、排泄及血浆蛋白结合实验。结果　大鼠 ig1 3 -甲基豆蔻酸 40 0 ,80 0 ,1 2 0 0 mg· kg-1后 ,拟合的血药浓度 -时间曲线符合二室模型 ,t1/2α 为 2 .3 1 3～ 2 .843 h,t1/2β 为5 .0 99～ 6 .3 3 9h;tpeak 为 2 .2 1 5～ 2 .76 6 h;血浆蛋白结合率大于 85 .80 %。药物在大鼠体内分布广泛 ,其中心、肺、脾、肝等组织浓度较高 ,肌肉、脂肪等组织相对较低。 2 4 h粪、尿、胆汁原形药物排泄量分别为给药量的1 3 .77% ,0 .0 0 3 2 %和 0 .0 2 1 4%。结论　 1 3 -甲基豆蔻酸在大鼠体内吸收快 ,达峰时间短 ,组织分布广泛 ,血浆蛋白结合率高 ;有部分原形药物从粪便排泄     

头孢呋辛钠在小鼠体内的药代动力学及组织分布研究

目的：通过HPLC探讨注射用头孢呋辛钠在小鼠体内的药代动力学和组织分布。方法：小鼠单剂量背部推注头孢呋辛钠1000mg/kg,在不同时间取其血浆及各组织匀浆液经离心沉淀蛋白后,采用HPLC法测定其药代动力学及组织中药物浓度。结果：背部给药后血浆药—时曲线符合一室开放模型,头孢呋辛钠体内分布迅速,分布半衰期为0.6179h,消除半衰期为2.2098h,AUC为76.3199h.mg/mL,肺、肝脏及肾脏中药物浓度较高。结论：头孢呋辛钠在体内分布广、组织浓度高、消除半衰期。     

高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

三尖杉酯碱的代谢

本文报告³H-三尖杉酯碱在正常及肿瘤鼠体内的吸收、分布和排泄。静脉注射³H-三尖杉酯碱后,大鼠血中放射性迅速降低,快、慢两相的生物半衰期分别为3.5分钟和50分钟。给大鼠静脉注射³H-三尖杉酯硷,注射后15分钟时,药物在各组织中的分布以肾脏为最高,肝、骨髓、肺、心脏、胃肠、脾、肌肉次之,睾丸、血及脑较低。两小时后各组织中的药物浓度均迅速下降,但骨髓的下降较慢,在所有组织中药物浓度居于首位。24小时后则在所测组织中药物浓度均降到相当低的水平。³H-三尖杉酯碱在肿瘤小鼠体内的分布情况与正常大鼠的分布趋势大致相仿。³H-三尖杉酯碱在静脉注射后24小时自大鼠体内排出的总放射性,在尿相当于注射剂量的30.2%,在粪相当于16.6%,其中原型药共占14.5%。此外胆汁也是一条重要排泄途径。静脉注射后24小时可自胆汁排出剂量的24.5%,其中原型药占17.1%。该硷口服给药可迅速吸收入血,但吸收不完全。     

Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg^?) and intraportal (5 and 10 mg kg^?) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg^?) of the drug was significantly lower than that after intravenous administration (5 mg kg^?) of the drug (1000 vs 1270 μg min mL^?) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC_{0–8 h}) after oral administration (5 mg kg^?) of the drug was considerably smaller than that after intraportal administration (5 mg kg^?) of the drug (271 vs 1580 μg min mL^?) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC_{0–8 h} after oral administration (5 mg kg^?) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg^?) of the drug (271 vs 320 μg min mL^?), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.     

联苯双酯的吸收、分布、代谢和排泄

用高效液相层析和放射性同位素法研究了联苯双酯在大、小鼠体内的代谢及人的排泄。联苯双酯口服后吸收缓慢而不完全;静脉给药后t1/2β为5.78小时,分布容积较大,且易向脂肪组织转移。动物和人经口给药后,原形药物的70%左右自粪排出。自尿和胆汁排出者均为其代谢产物。体外温孵证明,联苯双酯可被肝脏迅速代谢。灌胃给药后用HPLC法很难测到血浆和组织中的药物,提示药物吸收后被迅速转化,可能存在明显的首过作用。     

Preliminary data on the pharmacokinetics of Glaziovine in man

Summary The pharmacokinetic parameters of Glaziovine, a pro-aporphine alkaloid with neuropharmacological properties, were investigated in healthy human volunteers. Glaziovine-¹⁴C 20 mg was administered in capsules (oral route) and in vials (i.v. route). Total radioactivity was measured in plasma, urine and faeces. When administered orally, peak plasma levels were encountered at 2 h. The cumulative urinary excretion of total radioactivity over a 24 h period was 38% after oral and 50% after i.v. administration. Investigation of metabolites in urine revealed Glaziovine glucuronide as the sole metabolite of the drug. By comparing the percentage of urinary excretion or the area under the plasma level-time curve (AUC) obtained in the first 24 hours after i.v. and oral administration, enteral absorption was found to range from 78 to 84%. Thus, glaziovine appears to show very high enteral absorption.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

Circadian Changes in the Pharmacokinetics and Pharmacodynamics of Azosemide in Rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CL_R) of azosemide was significantly faster (2.86 compared with 1.76 mL min^?1 kg^?1) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL_R of azosemide was significantly faster (3.64 compared with 0.79 mL min^?1 kg^?1) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Comparative evaluation of absorption,distribution, and excretion of YM758, a novel If channel inhibitor,between albino and non-albino rats

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of ¹⁴C-YM758 monophosphate.

2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC_{0–1 h} between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism.

3. The distribution of the radioactivity derived from ¹⁴C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively.

4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.     

Metabolic fate of the new Ca++-channel blocking agent (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate. Distribution, excretion and protein binding in rats and dogs

Distribution, excretion and protein binding of (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate (TA-3090) in rats and dogs were investigated after oral (30 mg/kg (rats), 2 mg/kg(dogs] and intravenous (3 mg/kg (rats), 0.2 mg/kg (dogs) administration of 14C-TA-3090. Plasma level of radioactivity in rats reached plateau (6.04 micrograms equiv. of TA-3090 free base/ml) 1 h after oral administration. The plateau level continued at least up to 6 h. The plasma concentration of the unchanged drug (free base) reached the maximum (425 ng/ml) at 45 min after oral administration, and then decreased with a half-life of 1.16 h. Plasma level of radioactivity after intravenous administration to rats rose gradually up to 1 h and thereafter it was kept constant for 6 h. Plasma concentration of the unchanged drug decreased with half-lives of 0.43 h (alpha phase) and 1.33 h (beta phase) after intravenous administration. In dogs, the peak level of plasma radioactivity after oral administration was 227 ng/ml at 1 h. The Cmax, Tmax and t1/2 of unchanged drug were 31 ng/ml, 1.34 h and 4.13 h, respectively. The plasma levels of total radioactivity and unchanged drug after intravenous administration to dogs were 146 and 142 ng/ml at 1 min, respectively. The t1/2 of the plasma radioactivity were 0.02 h (alpha) and 4.02 h (beta). Those of unchanged drug were 0.03 h (alpha) and 1.66 h (beta).(ABSTRACT TRUNCATED AT 250 WORDS)