3′-二甲氨基亚甲基葛根素在大鼠体内组织分布与排泄研究

目的:研究3′-二甲氨基亚甲基葛根素在大鼠体内的组织分布与排泄情况,了解药物在动物体内变化过程,为临床试验提供药代依据.方法:大鼠尾静脉注射3′-二甲氨基亚甲基葛根素(生理盐水溶液,剂量50 mg/kg),采用机械匀浆处理组织.排泄实验是在不同时间点收集全部粪、尿、胆汁样品.用经验证的LC/MS/MS联用测定各组织、粪、尿、胆汁中3′-二甲氨基亚甲基葛根素的含量.结果:大鼠给药后,12 d内从粪中收集到给药剂量的(13.6±2.8)%,尿液中回收到(65.4±11.5)%,粪尿合计(79.0±14.3)%,5 d内胆汁中收集到(14.8±4.4)%.3′-二甲氨基亚甲基葛根素在大鼠各组织中均检测到,大肠内容物、小肠内容物和肝中浓度较高.结论:3′-二甲氨基亚甲基葛根素广泛分布于大鼠各组织中,主要以原形经尿和粪便排泄.     

[3H]西达本胺在大鼠体内的排泄研究

目的:运用氧化燃烧炉预处理样品技术对[3H]西达本胺在大鼠体内的排泄进行研究;并运用同位素标记技术初步推断西达本胺在大鼠体内的代谢产物。方法:采用氧化燃烧炉处理[3H]西达本胺粪、尿、胆汁样品,用液闪计数仪测定其放射性水平。结果:方法学确证研究结果显示粪、尿、胆汁样品3H回收率基本为100%,精密度和准确度均小于10%。大鼠单次灌胃给[3H]西达本胺(1.2 mg/kg,1.24 mC i/kg),336 h后从粪中收集到给药剂量的(63.28±12.40)%,尿中收集到(18.77±3.21)%,粪尿合计(82.25±13.15)%;给药后48 h胆汁排泄出给药剂量的(4.28±2.72)%。另外,经HPLC仪收集纯化样品后测定放射性得到的色谱图发现在大鼠血浆、粪、尿和胆汁中均有西达本胺代谢物峰,原形药物在图谱上的放射性约占50%。结论:氧化燃烧法用于处理[3H]西达本胺的大鼠粪、尿、胆汁样品简便、准确。大鼠灌服给药后,在血浆、粪、尿和胆汁中均发现有西达本胺原形药物和代谢产物,约有一半以原形排出体外。     

厚朴酚与和厚朴酚在大鼠体内的药代动力学

目的　观察厚朴酚与和厚朴酚在Wistar大鼠体内的动力学过程。方法　用实验建立的RP -HPLC法测定大鼠灌胃给予上述两种成分后不同时间各组织和体液中药物的含量及其蛋白结合率 ,并计算其在血中的药代动力学。结果　建立的方法能够良好分离两种成分 ,浓度 -色谱响应间线性相关系数均 >0 .999,平均加样回收率 >90 % ;两种成分在大鼠体内代谢符合一级消除动力学二室开放模型 ,Cmax　分别为 0 .974和 0 .5 2 2mg·L-1,T1/ 2 β　为 3.136和 3.2 84h ,T1/ 2ka　　为 0 .16 0和 0 .2 6 1h ;进入体内后 ,主要滞留于胃肠内 ,其他主要分布于肝、肺、肾组织中 ;血浆蛋白结合率分别为 6 8.5 4 %和 5 3.81% ;以粪排出为主 ,尿和胆汁排出量只有约 5 %。结论　厚朴酚与和厚朴酚吸收较差 ,进入循环后以肝代谢和肾排泄为主。     

[~3H]-乙酰紫草素在小鼠体内的组织分布、排泄及血中分布研究

目的:用氧化燃烧炉样品预处理技术研究[3H]-乙酰紫草素在小鼠体内的组织分布、排泄和血中分布.方法:小鼠单次灌服[3H]-乙酰紫草素后,收集组织、血、尿和粪样,氧化燃烧炉法进行样品预处理,液闪计数仪测定放射性水平.结果:小鼠单次灌胃给[3H]-乙酰紫草素(120 mg/kg,2.96×107 Bq/kg)后,放射性主要分布在胃、肠,其次是胆囊、肝、肾、肺,脑和脊髓分布较少.271 h后从粪中收集到给药剂量的(68.5 ± 3.3)%,尿中收集到(17.6± 3.1)%,粪尿合计(86.1 ± 5.5)%.另对乙酰紫草素在血中存在形式、血细胞和血浆中的分配比例以及与血浆蛋白结合的形式、结合率进行了探索性研究.结论:乙酰紫草素吸收较差;组织分布广泛;排泄较完全;1 h血样中没有检测到原形;血浆、血细胞药物含量分配比约为4∶ 1;人血浆蛋白结合率高;血浆蛋白的结合为共价和疏水作用两种形式并存.     

紫檀芪在正常及模拟失重大鼠尿液及粪便中的排泄研究

目的研究紫檀芪(pterostilbene,PTS)在正常及模拟失重大鼠尿液及粪便中的排泄规律。方法正常对照大鼠和尾吊21 d模拟失重后大鼠,灌胃给予33 mg/kg PTS,采用LC-MS法测定各时间段尿粪样本中PTS含量,获取PTS在尿粪中排泄百分比及排泄量数据。结果正常对照大鼠给药48 h内,PTS在尿粪中排泄速度较慢,给药72 h后,PTS在尿粪中的累计排泄量分别为(2.16±0.26)μg、(2.11±0.26)μg,占给药剂量的(0.25±0.04)‰、(0.24±0.03)‰。与对照组相比,PTS在模拟失重大鼠尿粪中排泄量显著增高。给药72 h后,PTS在尿粪中的累计排泄量分别为(4.39±0.83)μg、(3.83±0.69)μg,占给药剂量的(0.63±0.13)‰、(0.56±0.09)‰。结论 PTS在正常和模拟失重21 d大鼠体内,尿液及粪便排泄量存在显著差异,模拟失重状态显著影响PTS在大鼠尿液及粪便的排泄过程。     

基因重组人白介素—3在小鼠中的药动学,分布和排泄的特点

每只小鼠皮下注射１．８μｇ／（药相当于９０μｇ／ｋｇ）的＾１２５Ｉ标记基因重组人白介素－３（＾１２５Ｉ－ｒｈＩＬ－３０）后，用相反高效液相色谱法（ＲＨＰＬＣ）测定血浆浓度，估算动力学参数和测定组织放射性分布．消除半衰期为１．７３ｈ，药物在血浆内迅速降解。组织放射性分布特点为：肾泌尿排泄系统浓度最高，胆汁，肠道系统略高于血浆，淋巴、骨髓和脾脏等浓度略低或与血浆接近，脑内含量最低。４８ｈ内经尿和粪排泄     

HPLC-MS / MS 法测定抗抑郁新药阿姆西汀在大鼠体内的组织分布简

目的研究抗抑郁新药阿姆西汀（S-071031B）在大鼠体内各组织的分布特点。方法雄性sD大鼠随机分组,单剂量（20mg·kg-1）灌胃给药后,分别于15min、2、6和24h处死取血并解剖主要组织,采用LC—MS／MS测定阿姆西汀在生物样品中的药物浓度。结果sD大鼠灌胃给药15min后即在胃、小肠和肝脏组织中药物浓度达峰值,给药6h后在睾丸组织中药物浓度达峰值。而在心脏、脾脏、肺脏、肾脏、脑、肌肉组织及血浆均在给药后2h达到峰值,24h后各组织中药物浓度均降至较低水平。结论阿姆西汀在大鼠体内吸收迅速,人血后可广泛分布到体内各组织中,药物在体内也快速消除,无组织蓄积作用,具有良好的开发前景。     

眼镜蛇毒因子的体内过程及药物代谢动力学研究

目的:探讨眼镜蛇毒因子的体内过程及其药物代谢动力学。方法:本文采用氯胺T氧化法,制备了~(125)Ⅰ眼镜蛇毒因子作示踪剂对“眼镜蛇毒因子(CVF)”的体内过程及药物代谢动力学进行了研究。结果:静脉注射后,大鼠体内血药浓度时间曲线为二房室模型,T_(1/2)β为18.14h。小鼠尾静脉注射1h后,各脏器(除肌肉外)放射性活性达到峰值,其值(％)大小顺序如下:肾(15.93)>脾(10.66)>心(9.38)>肝(1.32)>肺(0.77)>脑(0.38)。~(125)Ⅰ-CVF静脉注射后,72h内尿排泄率达74.3％,而粪排泄率为7.02％。结论:眼镜蛇毒因子的体内过程符合二房室模型,静脉注射后主要从尿中排泄。     

人尿源性激肽释放酶在家兔和大鼠中的药代动力学

目的　研究兔和大鼠静脉注射125I-激肽释放酶后的药代动力学。方法　125I标记结合分子排阻高效液相(SHPLC)。结果　125I-激肽释放酶保持酶解生色底物S-2266的生物活性,放化纯度(95.2±1.8)%。家兔静脉注射5×10-3、15×10-3和45×10-3pNAU*kg-1剂量125I-激肽释放酶后与血浆蛋白质结合,t1/2α为0.09～0.15h,t1/2β为1.28～2.18h。曲线下面积与剂量成正比,而全身清除率相近。大鼠三氯醋酸(TCA)可沉淀放射性,分布特点是泌尿排泄系统最高,血管丰富内脏组织较高,脑皮层最低。大鼠静脉注射125I-激肽释放酶后主要经尿排泄,少量经粪排泄;48h尿粪排出(96.9±3.3)%;12h胆汁排出(7.9±1.8)%。125I-激肽释放酶与兔血浆蛋白质结合的Bmax为(94.3±0.77)%,Kd为8.9×10-8mol*L-1。结论　家兔静脉注射125I-激肽释放酶后符合线性药代动力学,大鼠静脉注射125I-激肽释放酶后不能进入血脑屏障。     

尿L-岩藻糖测定的临床意义

每只小鼠皮下注射１．８μｇ／（约相当于９０μｇ／ｋｇ）的１２５Ｉ标记基因重组人白介素－３（１２５Ｉ－ｒｈＩＬ－３）后，用反相高效液相色谱法（ＲＨＰＬＣ）测定血浆浓度，估算动力学参数和测定组织放射性分布。消除半衰期为１．７３ｈ，药物在血浆内迅速降解。组织放射性分布特点为：肾泌尿排泄系统浓度最高，胆汁、肠道系统略高于血浆，淋巴、骨髓和脾脏等浓度略低或与血浆接近，脑内含量最低。４８ｈ内经尿和粪排泄的放射性占注入量（８４．０±９．２）％，其中尿（７１．９±６．７）％，粪（１２．２±５．３）％。肾脏是降解１２５Ｉ－ｒｈＩＬ－３的重要器官之一。     

Biological distribution and excretion of DTPA labeled with Tc-99m and In-111

For the purpose of radiation dose estimates, organ assays and excretion measurements of the Tc-99m and In-111 complexes with DTPA were conducted in dogs at various time intervals up to 24 hr, and the results compared with available human data. The peak concentration of the Tc-99m complex, at 3 min after injection, was 5% of the administered dose for one kidney, 3.5% for the liver, and 3.5% for the small bowel. No organ system except the urinary tract reached a concentration higher than that in blood for several hours after the injection. The biliary excretion of these agents was extremely low, and their elimination in the feces was negligible. In man, it appears that the residual 4-5% of an administered dose not eliminated in the urine by 24 hr is widely distributed in various tissues. The distribution of the In-111 complex is similar but not identical to that of the Tc-99m complex.     

Synthesis of [76Br]bromofluorodeoxyuridine and its validation with regard to uptake, DNA incorporation, and excretion modulation in rats.

This investigation aimed to validate 5-[76Br]bromo-2'-fluoro-2'-deoxyuridine (BFU) as a proliferation marker using PET. METHODS: Five megabecquerels 76Br-BFU were injected into the tail vein of Sprague-Dawley rats. At 6 or 16 h after injection, the rats were killed and the radioactivity concentration was measured in 6 different organs and blood. The fraction of radioactivity incorporated into DNA was determined for the spleen and small intestine. In parallel experiments, the animals were pretreated with hydroxyurea. In a few experiments, the urinary excretion of radioactivity was measured from administration of 76Br-BFU until 6 h. A sample of urine was analyzed with HPLC. In separate experiments, rats were given different doses of cimetidine, and the organ uptake and the fraction of radioactivity in DNA were determined at 24 h. RESULTS: The highest organ uptake of radioactivity was found in the spleen, followed by the small intestine. Approximately 90% of the radioactivity in these organs was incorporated into DNA, and inhibition by hydroxyurea was pronounced. Intact tracer constituted more than 95% of the radioactivity in urine. With cimetidine, the uptake of radioactivity increased approximately 2-5 times at different doses, whereas the urine radioactivity decreased markedly. CONCLUSION: 76Br-BFU was predominantly incorporated into DNA after administration in vivo in rats. If cimetidine was given in combination with the tracer, an increased contrast of radioactivity concentration between organs of high proliferation and organs of low proliferation was observed. The investigation suggested that 76Br-BFU has good potential as a PET tracer for the assessment of proliferation in vivo.     

七十味珍珠丸中有毒重金属在比格犬体内的分布和排泄

目的 研究长期服用藏成药七十味珍珠丸后主要有毒重金属在动物体内的分布和排泄.方法 以七十味珍珠丸高剂量喂服比格犬,给药12周后和停药4周后检测动物血液和排泄物中有毒重金属元素的含量,并与正常对照组比较.结果 比格犬给予七十味珍珠丸后主要重金属元素在血中的浓度均有所升高,停药后降低;重金属元素在排泄物中的浓度显著升高;主...     

Gadolinium-ethoxybenzyl-DTPA, a new liver-specific magnetic resonance contrast agent. Kinetic and enhancement patterns in normal and cholestatic rats.

OBJECTIVES. Gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) is a new hepatobiliary magnetic resonance imaging (MRI) contrast agent with a dual elimination: 70% via the liver and bile and 30% via the kidney in normal rats. The abdominal enhancement patterns of this new compound and the uptake mechanism by the liver were studied in rats using tissue relaxometry and MRI. METHODS. Twelve normal rats, 33 rats treated with agents designed to inhibit biliary excretion of the agent, and 6 rats with surgically ligated common bile ducts received Gd-EOB-DTPA intravenously. Distribution and excretion were measured by MR relaxometry. MR signal intensity was measured over time for liver, kidney, and bowel. RESULTS. In normal animals, 0.1 mmol/kg Gd-EOB-DTPA induced a significantly greater (200%) and more prolonged liver signal enhancement (100% at 30 minutes) than Gd-DTPA at the same dose. Either hyperbilirubinemia, induced by common bile duct ligation, or bromosulfophtalein (BSP) infusion inhibited liver uptake of Gd-EOB-DTPA, resulting in a preferential elimination via the kidney. Taurocholate (TC), an inhibitor of the bile acid transporter, was unable to block the liver uptake of Gd-EOB-DTPA. Blood half-lives of Gd-EOB-DTPA in rats were 2.4 minutes for the first component and 8.2 minutes for the second. CONCLUSIONS. Data indicate that transport of Gd-EOB-DTPA through the liver into bile is driven by the organic anion transporter. The relation between enhancement of liver and kidney may be diagnostically useful to indirectly evaluate liver excretory function. Yet, persistent enhancement of liver, even in the presence of severe hyperbilirubinemia, should be sufficient to identify focal mass lesions.     

Pharmacokinetics and renal handling of 99mTc-labeled peptides.

99mTc-labeled peptides, particularly those of a lipophilic nature, are often excreted through the hepatobiliary system, and the subsequent accumulation in the intestine may obscure receptor-mediated uptake in tumor sites in the pelvis. We have therefore explored the route and rate of excretion of a small series of Tc-labeled peptides to shed some light on the mechanisms that influence the clearance of these agents. METHODS: Pharmacokinetic parameters, biodistribution, routes of elimination of 99mTc-complexes of 3 model tetrapeptides--namely, acetyl-N-Gly-Gly-Cys-Gly (AGGCG), acetyl-N-Ser-Ser-Cys-Gly (ASSCG), and acetyl-N-Gly-Gly-Cys-Lys (AGGCL)--were determined in rats in vivo. Renal handling of the complexes was studied in the perfused rat kidney. RESULTS: After intravenous injection, a relatively fast disappearance of the complexes from blood was found. Although the parameters of distribution in all 3 chelates were very similar, the elimination rate of 99mTc-AGGCG was higher than those of 99mTc-ASSCG and 99mTc-AGGCL. The Tc complexes under study were distributed mainly to the excretory organs (kidneys and liver), and no specific accumulation in other organs or tissues was found. Most of the radioactivity after intravenous administration of the chelates was rapidly eliminated through the urine, but a significant amount was also excreted through the feces, in the following order among the 3 chelates: 99mTc-AGGCL < 99mTc-ASSCG < 99mTc-AGGCG. Different proportions of glomerular filtration and secretion in renal tubules of the complexes were found in the perfused rat kidney. Elimination by glomerular filtration was dominant only in the case of 99mTc-AGGCL, whereas the rate of filtration of 99mTc-AGGCG was very low because of its high protein binding. Various rates of secretion into renal tubules were shown for all 3 agents. This renal excretion pathway was decisive in 99mTc-AGGCG and lowest in 99mTc-AGGCL. 99mTc-ASSCG was eliminated by both mechanisms at similar rates. CONCLUSION: These studies show that increasing the hydrophilic nature or reducing the negative charge of the peptides will reduce their hepatobiliary excretion, whereas the incorporation of suitable peptide sequences permits them to exploit efficient routes of renal excretion, such as tubular secretion, thereby optimizing the pattern of biodistribution of these radiopharmaceuticals.     

Tissue distribution and magnetic resonance spin lattice relaxation effects of gadolinium-DTPA

Gadolinium-DTPA complex (Gd-DTPA) is a potential clinical magnetic resonance (MR) contrast agent that enhances images primarily by decreasing spin-lattice relaxation time (T1) in tissues in which it localizes. This study was designed to determine the immediate tissue distribution of intravenously administered Gd-DTPA in selected organs of interest as a function of administered dose and tissue Gd-DTPA concentration. An intravenous bolus of Gd-DTPA with a tracer quantity of Gd-153 was administered to three groups of rabbits at the following doses: 0.01 mM/kg (n = 6); 0.05 mM/kg (n = 6); 0.10 mM/kg (n = 6). A control group received sham injections. Five minutes after Gd-DTPA was administered, all animals were killed; samples of serum, lung, heart, kidney, liver, and spleen were analyzed in a 0.25 T MR spectrometer to measure T1, and then in a gamma well counter to determine tissue concentration of Gd-DTPA. Tissue distribution (per cent dose/tissue weight in g) at five minutes after injection was proportionally constant over the range of doses given. Tissue concentration varied linearly with injected dose (r greater than 0.98 for all tissues). Relaxation rate (1/T1) varied linearly with injected dose and with tissue Gd-DTPA concentration (r greater than 0.97 for all tissues). The order of tissue relaxation rate response to a given dose was: kidney greater than serum greater than lung greater than heart greater than liver greater than spleen. We conclude that because of its extracellular distribution and linear relaxation rate versus concentration relationship, Gd-DTPA enhancement in MR images may be a good marker of relative organ perfusion.     

Biodistribution and excretion of radioactivity after the administration of 166Ho-chitosan complex (DW-166HC) into the prostate of rat

Purpose The objective of this study was to determine the fate of the ¹⁶⁶Ho-chitosan complex (DW-166HC) in rats by examining its absorption, distribution and excretion after administration into the prostate.Methods About 100 Ci of DW-166HC [containing 0.1875 mg of Ho(NO₃)₃·5H₂O and 0.25 mg of chitosan] was administered intraprostatically. The level of radioactivity in blood, urinary and faecal excretion, and radioactivity distribution were examined. To determine the effect of chitosan in DW-166HC, ¹⁶⁶Ho nitrate alone [0.1875 mg of Ho(NO₃)₃·5H₂O] was administered into the prostate of male rats, and radioactivity distribution was examined using whole-body autoradiography.Results After administration of DW-166HC into the prostate, cumulative urinary and faecal excretion over the period 0–72 h was 0.35% and 0.11%, respectively. The radioactivity at the administration site was extremely high at all time points up to 144 h (>98% of injected dose). The small amount of radioactivity which did transfer from the administration site distributed mainly to the liver, spleen, kidney cortex and bone. Compared with the DW-166HC group, the group that received ¹⁶⁶Ho nitrate alone displayed three- to fourfold higher levels of radioactivity in the main tissues, including liver, spleen, kidney cortex and bone, at 24 h after administration (P<0.05).Conclusion The results of this study show clearly that most of the administered DW-166HC remained at the administration site. It is concluded that the chitosan complex may be used to retain ¹⁶⁶Ho within a limited area in cancer of the prostate.     

Ferrioxamine B derivatives as hepatobiliary contrast agents for magnetic resonance imaging.

Succinyl (SDF), phenylsuccinyl (PSDF), glutaryl (GDF), and phenylglutaryl (PGDF) derivatives of desferrioxamine B (DF) have been synthesized. In rats given the 59Fe(III) chelates of each these ligands at tracer levels, 82-94% of the 59Fe was eliminated within 1-2 days. 59Fe given as DF, SDF, and GDF chelates was excreted primarily in the urine, while nearly 50% of that given as PSDF and PGDF was excreted in the feces. Correspondingly, Fe-DF, Fe-SDF, and Fe-GDF (0.2 mmol/kg) produced early, marked renal, but no gastrointestinal magnetic resonance imaging (MRI) enhancement. Fe-PSDF and Fe-PGDF (0.2 mmol/kg) produced marked and rapid MRI enhancement of the upper small intestine. In animals with cannulated bile ducts, 59Fe from 59Fe-PGDF (carrier added, 0.1 mmol/kg) appeared rapidly in the collected bile, but not in the intestinal contents, proving that the contrast agent reaches the bowel via the bile. These changes in the excretion and MRI enhancement patterns brought about by the presence of a phenyl substituent apparently were not related to changes in lipophilicity or protein binding.     

Biodistribution, PET, and radiation dosimetry estimates of HSV-tk gene expression imaging agent 1-(2'-Deoxy-2'-18F-Fluoro-beta-D-arabinofuranosyl)-5-iodouracil in normal dogs.

FIAU is of interest as a potential reporter probe to monitor herpes simplex virus thymidine kinase (HSV-tk) gene expression and bacterial infections. This study investigates the biodistribution, metabolism, and DNA uptake of 1-(2'-deoxy-2'-(18)F-fluoro-beta-d-arabinofuranosyl)-5-iodouracil ((18)F-FIAU) in normal dogs. METHODS: Four normal dogs were intravenously administered (18)F-FIAU. A dynamic PET scan was performed for 60 min over the upper abdomen; this was followed by a whole-body scan for a total of 150 min on 3 dogs. The fourth dog was not scanned and was euthanized at 60 min. Blood and urine samples were collected at stipulated time intervals and analyzed by high-performance liquid chromatography to evaluate tracer clearance and metabolism. Tissue samples collected from various organs were analyzed to evaluate tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. Nondecay-corrected time-activity curves were used for residence time calculation and absorbed dose estimation. RESULTS: At 60 min after injection, unmetabolized FIAU radioactivity in blood and urine samples was greater than 78% and 63%, respectively, demonstrating resistance to metabolism. The tissue-to-muscle ratio derived from image and tissue analysis showed a slightly higher uptake in proliferating organs (mean tissue-to-muscle values: small intestine, 1.97; marrow, 1.70) compared with nonproliferative organs (heart, 1.07; lung, 1.06). A high concentration of activity was seen in the bile (mean, 23.02), demonstrating hepatobiliary excretion of the tracer. Extraction analysis of tissue samples showed that >62% of the activity in the small intestine, 74% in marrow, and <21% in heart, liver, and muscle was incorporated into DNA. CONCLUSION: These results demonstrate that FIAU is resistant to metabolism and moderately incorporates into DNA in proliferating tissues. These results suggest that incorporation into the DNA of normal tissues may need to be considered when FIAU is used to track reporter gene activity. Studies in humans are needed to determine whether imaging properties differ in patients and are altered as a result of metabolism changes affected by gene therapies.