Comparison of the effectiveness of several chelators after single administration on the toxicity,excretion, and distribution of cadmium

The effect of several chelating agents (diethyldithiocarbamic acid, DDC; nitrilotriacetic acid, NTA; 2,3-dimercaptopropanol, BAL; dl-penicillamine, PEN; 2,3-dimercaptosuccinic acid, DMSA; ethylenediaminetetraacetic acid, EDTA; and diethylenetriaminepentaacetic acid, DTPA) on the toxicity, excretion, and distribution of Cd was determined in male Swiss Webster mice weighing 30–45 g. Chelators were administered intraperitoneally at a dose equal to one-fourth of their respective LD50. To determine the effect of the various chelators on the toxicity of Cd, various doses of CdCl₂ (4–10 mg Cd/kg, iv) were given, followed immediately by one of the chelators. Survival was recorded at the end of 14 days. Significant increases in survival were noted with DMSA, EDTA, and DTPA, with DTPA being the most effective. Radiolabeled Cd (¹⁰⁹CdCl₂, 1 mg Cd/kg, iv) was used in a 24-hr excretion and distribution study. The chelators were given immediately after the Cd. DTPA, followed by EDTA and then DMSA, was consistently the most effective in increasing the urinary excretion of Cd and reducing the concentration of Cd found in various tissues. NTA, BAL, DDC, and PEN had no orerall beneficial effects. DTPA appears to be the most effective agent of those tested in the prevention of acute Cd intoxication.     

Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats

Spinosin is the major effective single constituent in the traditional Chinese herb Semen Ziziphi Spinosae, which is used for sedation and hypnosis. For the further use of spinosin in treating insomnia, the pharmacokinetics and tissue distribution of spinosin after intravenous administration to rats was investigated. An HPLC method with an ODS column (250 mm x 4.6 mm, i.d.) and a mobile phase of acetonitrile-water-acetic acid (23:77:1) was used for the determination of spinosin in the plasma and tissues of rats. Vanillin was used as an internal standard, and spinosin was detected at 334 nm. The calibration curve of spinosin in plasma showed good linearity over the concentration range of 1-300 microg/ml, and the quantitation of limit of plasma was 1 microg/ml. The linear range of concentrations of spinosin in the heart, spleen, stomach, lung, testis, brain, and intestine was 0.1-40 microg/ml and the quantitation limit was 0.1 microg/ml. The linear range of concentrations of spinosin in the liver and kidney was 1-150 microg/ml, and the quantitation limit was 1 microg/ml. The correlation coefficients of all calibration curves were between 0.9939 and 0.9980. The intra and interrun precision for all samples was less than < or =11.0%. The time-concentration curve of spinosin after the intravenous administration of a single dose of 20 mg/kg to rats corresponded to the two-compartment model. The main pharmacokinetic parameters T(0.5alpha), T(0.5beta), CLs, AUC(0-T), and V(c) were 6.66 min, 51.5 min, 1.42 l.min(-1), 2.83 mg.min.ml(-1), and 14.0 l.kg(-1), respectively. At 20 min, a concentration peak occurred in liver and brain tissues. The highest level of spinosin occurred in the liver, followed by the spleen and kidney. The lowest level of spinosin appeared in the testis, followed by the brain. Spinosin was not detected in smooth and skeletal muscle. After intravenous administration, the drug was distributed extensively and transferred quickly in rats in vivo.     

The relationship of metallothionein to the toxicity of cadmium after prolonged oral administration to rats

Male Sprague-Dawley rats were exposed to cadmium at concentrations of 10, 30, and 100 ppm in their drinking water for 24 weeks. The testicular function, blood pressure, heart rate, EKG, hematocrit, blood hemoglobin, plasma glucose, aniline hydroxylase, hexobarbital oxidase, cytochrome P-450, concentration of Cd in the tissues, concentration of metallothionein in the kidney and liver, organ weights, bone calcification, and histopathology of all the rats were recorded after 3, 6, 12, and 24 weeks. In addition, the weight gain, food and water intake, urine flow and protein excretion, and motor activity were measured weekly in the 24-week group. CNS function was assessed by measuring the motor activity. The hourly nocturnal and daily motor activities decreased with time for the 30- and 100-ppm rats when compared to the control rats. Renal injury was indicated by an increase in the concentration of protein in the urine with time for the 30- and 100-ppm rats when compared to the control rats. There was also slight and focal tubular necrosis in the 30- and 100-ppm rats by Week 24. The time- and dose-dependence of the concentration of the Cd in the intestine indicates that the suggested protective mechanism of intestinal metallothionein, where metallothionein sequesters dietary Cd in the mucosal cells and thus hinders the transfer of the metal to the systemic circulation, is quickly overloaded at concentrations of 10 ppm or less of Cd in the drinking water. The concentration of metallothionein and Cd in the kidney and liver increased with dose at all time intervals and increased with time at most doses. However, the rate of increase of the concentration of metallothionein and Cd in the liver and kidney was not the same. In the liver ratio of Cd to Cd-binding capacity of metallothionein reached a plateau with time, which may explain hepatic tolerance to Cd. On the other hand, in the kidney, were necrosis and dysfunction were observed, the ratio continued to increase with time.     

应用整体自显影定量技术开展的单多次给药后大鼠组织分布比较研究

目的:应用整体自显影定量技术(QWBA),比较单次和重复多次给药后大鼠体内的组织分布情况,以指导人体放射性物质平衡试验设计.方法:按15 mg ? kg-1剂量,分别灌胃给予雄性Long-Evans(LE)大鼠0,7和14次的非放射性标记药物VPS-01(qd)24h后单次灌胃给予100 μCi/15 mg?kg-1的...     

Pulmonary toxicity and extrapulmonary tissue distribution of metals after repeated exposure to different welding fumes

Welders are exposed to fumes with different metal profiles. The goals of this study were to compare lung responses in rats after treatment with chemically different welding fumes and to examine the extrapulmonary fate of metals after deposition in the lungs. Rats were treated by intratracheal instillation (0.5?mg/rat, once a week for 7 weeks) with gas metal arc–mild steel (GMAW-MS) or manual metal arc–hardsurfacing (MMAW-HS) welding fumes. Controls were treated with saline. At 1, 4, 35, and 105 days after the last treatment, lung injury and inflammation were measured, and elemental analysis of different organs was determined to assess metal clearance. The MMAW-HS fume was highly water-soluble and chemically more complex with higher levels of soluble Mn and Cr compared to the GMAW-MS fume. Treatments with the GMAW-MS fume had no effect on toxicity when compared with controls. The MMAW-HS fume induced significant lung damage early after treatment that remained elevated until 35 days. Metals associated with each fume sample was cleared at different rates from the lungs. Mn was cleared from the lungs at a faster rate and to a greater extent compared to the other metals over the 105-day recovery period. Mn and Cr in the MMAW-HS fume translocated from the respiratory tract and deposited in other organs. Importantly, increased deposition of Mn, but not other metals, was observed in discrete brain regions, including dopamine-rich areas (e.g., striatum and midbrain).     

Flavonoid pharmacokinetics and tissue distribution after repeated dosing of the roots of Scutellaria baicalensis in rats

Scutellariae Radix (root of Scutellaria baicalensis, SR) contains numerous flavonoids such as baicalin, baicalein, and wogonin. This study investigated the pharmacokinetics and tissue distribution of flavonoids and their metabolites in rats after repeated dosing of a SR decoction. Sprague-Dawley rats were orally administered SR at 2 g/kg for seven doses. After the 7th dose, blood samples were withdrawn at specific times and organs, including the liver, kidney, lung, and brain, and collected. The concentrations of baicalein and wogonin in the serum and various tissues were assayed by HPLC before and after hydrolysis with glucuronidase and sulfatase. Baicalein and wogonin were not detected in the serum, and the molecules found were their glucuronides/sulfates. In tissues, the free forms of baicalein and wogonin appeared in the liver, kidney, and lung in addition to their glucuronides/sulfates. Baicalein was the major form in the lung, whereas baicalein glucuronides/sulfates were the major forms in the liver and kidney. Wogonin was the major form in the liver, kidney, lung, and traces of wogonin glucuronides/sulfates were detected in the kidney and liver. Neither baicalein and wogonin nor their glucuronides/sulfates were detected in the brain. In conclusion, the glucuronides/sulfates of baicalein and wogonin were exclusively present in the circulation, whereas their free forms appeared in the lung, liver, and kidney.     

大鼠口服东莨菪素后的组织分布和排泄特征研究(英文)

研究东莨菪素在大鼠体内的组织分布和排泄特征,SD大鼠灌胃东莨菪素(50mg/kg),分别于给药后5,15,30,60,120,240分钟取大鼠心、肝、脾、肺、肾、肌肉、脂肪、脑、睾丸、子宫、胃、小肠等组织器官测定其原形药物浓度。结果表明,东莨菪素广泛分布于各组织器官且于给药后15分钟浓度即达峰值,其中肝、肾、胃和小肠含量较高。此外,东莨菪素在胆汁、尿液、粪便的排泄研究显示,胆汁、尿液、粪便的累积排泄量分别为0.032%,3.752%和0.784%。表明东莨菪素在大鼠体内主要以代谢物的形式消除。     

Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration

This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4-8.2 min and 38.6-62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1-123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6-6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration-time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0-5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.     

The influence of high dietary zinc on tissue disposition and urinary excretion of cadmium,zinc, copper and iron after repeated parenteral administration of cadmium to rats

The administration of a high dietary supplement of zinc sulphate (2000 ppm) to rats for 28 days produced no effect upon growth rate of the animals but caused an increased food intake. The supplement had no effect upon the reduction of growth rate caused by the daily injection of cadmium chloride (1.5 mg/kg). Zinc-supplemented animals showed an increased accumulation of zinc in the liver and kidney, plasma zinc levels were significantly increased and there was an elevated excretion of zinc in the urine compared to control animals. Cadmium-treated, zinc-supplemented animals had a higher concentration of cadmium in the liver compared to animals treated only with cadmium. The high dietary zinc did not interfere with tissue or plasma concentration of copper and iron, nor did it influence the cadmium-induced changes in these metals. There was some indication however of a decreased urinary excretion of copper.     

Effects of mucosal metallothionein in small intestine on tissue distribution of cadmium after oral administration of cadmium compounds.

The effect of mucosal metallothionein (MT) preinduced by zinc (Zn) on tissue distribution of cadmium (Cd) after administration of Cd with several chelating agents was studied in rats. After Cd-cysteine (Cd-Cys) was incubated with intestinal Zn-MT in vitro, all the Cd dissociated from Cys and exchanged the Zn bound to MT. However, dissociation of Cd bound to EDTA (Cd-EDTA) was not observed in the incubation mixture containing intestinal Zn-MT. The concentration of Cd in intestinal mucosa reached a maximum 16 hr after oral administration of Cd-Cys. The Cd level in the intestine was higher than that in the liver and kidney and was similar to that occurring after oral administration of CdCl2. The amount of Cd distributed to the liver and kidney after Cd-EDTA administration was about 30% of the level after CdCl2 administration. Even at 15 mg Cd/kg Cd-EDTA, the Cd level in the intestinal mucosa reached a plateau after 2-4 hr, as it did in the liver and kidney. When Cd-Cys was administered po to control or to Zn-pretreated rats, it was found that Zn pretreatment increased the concentration of Cd in the kidney, as was the case after oral administration of CdCl2. This effect of Zn pretreatment was not observed after oral administration of Cd-EDTA. When Cd-MT was injected into the duodenum, the intestinal absorption of Cd was 60% of that after CdCl2 administration. After the duodenal administration of Cd-MT, at all doses, the concentration of Cd in the kidney was higher than that in the liver. These results suggest that mucosal MT in the small intestine might trap Cd absorbed from the intestinal lumen and transport it to the kidney.     

Tissue distribution of cadmium and nephropathy after administration of cadmium in several chemical forms

Cadmium (Cd) was administered as CdCl2, Cd-Cys, Cd-partial structural peptide of metallothionein (MT) II, Cd-MT I, and Cd-MT II to rats, and the distribution of and nephropathy caused by the corresponding Cd compounds were examined. Each Cd complex showed dissociation of Cd in vivo and in vitro in the plasma. With Cd-Cys approximately 80% dissociation was observed while Cd-MT showed only 15% dissociation. When the dissociation of the Cd complex in the plasma was less, the distribution of Cd to the liver was decreased but distribution was increased to the kidney and urine. Each Cd complex showed the presence of Cd in the kidney shortly after the administration in the high molecular weight fraction (HM-fr) and also in MT-fr. This was then followed by a decrease in the Cd level in the HM-fr but by an increase in the MT-fr. All Cd compounds except CdCl2 caused some transient renal damage. Renal damage shown by significant increases of urinary protein, glucose, and amino acids were observed at the doses of 1.3-1.7 mg Cd/kg in the Cd-Cys group, at 0.51-0.64 mg Cd/kg in the Cd-peptide group, and at 0.16-0.23 mg/kg in the Cd-MT I and II groups. The Cd level in the kidney of rats with renal damage from these complexes was approximately the same in all the groups, that is, 10 micrograms/g kidney. It is concluded that Cd causes renal damage when its concentration in the kidney is 10 micrograms/g or higher regardless of the type of Cd complex that is administered.     

The effect of repeated administration of several chelators on the distribution and excretion of cadmium

The effect of repeated administration of several chelators on the distribution and excretion of cadmium (Cd) was determined in male Swiss Webster mice. Radioisotopic Cd (¹⁰⁹Cd, 1 mg Cd/kg) was administered iv; 48 hr later (after maximal induction of hepatic metallothionein) daily chelation therapy was initiated. Mice received one of the following ip treatments for 5 days: saline, diethyldithiocarbamic acid (DDC), nitrilotriacetic acid (NTA), 2,3-dimercaptopropanol (BAL), d,l-penicillamine (PEN), 2,3-dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA), or diethylenetriaminepentaacetic acid (DTPA). Mice were housed in metabolic cages, and urine and feces were collected daily for 7 days. After 5 days of chelation therapy (7 days after Cd), the mice were killed and various organs removed. DTPA, EDTA, DMSA, and BAL significantly increased the excretion of Cd into urine. DDC significantly increased the fecal elimination of Cd and altered tissue concentrations of Cd. The concentration of Cd in DDC-treated mice was increased in testes, muscle, and brain and decreased in kidney, spleen, and blood. The observed increase in urinary excretion of Cd when certain chelators were administered after the induction of hepatic metallothionein suggests that increasing the duration of chelation therapy may decrease the concentrations of Cd in tissues and hence, reduce the toxicity of the metal.     

Toxicokinetics and tissue distribution of prothioconazole in male adult Sprague-Dawley rats following a single oral administration

Abstract

1. Prothioconazole (PTC) is a new type of triazolinthione fungicide used worldwide. Despite its widespread use, the basic toxicokinetics (TK) information for health risk assessments of PTC is limited.

2. TK behavior and metabolism studies of PTC were performed in male adult Sprague Dawley (SD) rats after a single oral administration. Serial blood and tissue samples were analyzed for their PTC content by high-performance liquid chromatography (HPLC) to obtain comprehensive time-course data for estimation of TK parameters.

3. PTC was rapidly but incompletely absorbed from the gastrointestinal tract of fasted adult rats. It was widely distributed in all parts of body, but demonstrated little tendency to accumulate. And PTC was excreted mainly in the form of parent compound.

4. The detection of PTC in brain and testis proved that further investigations are required to determine whether PTC could result in neurotoxicity and male reproductive toxicity.     

Comparative toxicity of silicon dioxide,silver and iron oxide nanoparticles after repeated oral administration to rats

Although silicon dioxide (SiO₂), silver (Ag) and iron oxide (Fe₂O₃) nanoparticles are widely used in diverse applications from food to biomedicine, in vivo toxicities of these nanoparticles exposed via the oral route remain highly controversial. To examine the systemic toxicity of these nanoparticles, well‐dispersed nanoparticles were orally administered to Sprague–Dawley rats daily over a 13‐week period. Based on the results of an acute toxicity and a 14‐day repeated toxicity study, 975.9, 1030.5 and 1000 mg kg^–1 were selected as the highest dose of the SiO₂, Ag and Fe₂O₃ nanoparticles, respectively, for the 13‐week repeated oral toxicity study. The SiO₂ and Fe₂O₃ nanoparticles did not induce dose‐related changes in a number of parameters associated with the systemic toxicity up to 975.9 and 1000 mg kg^–1, respectively, whereas the Ag nanoparticles resulted in increases in serum alkaline phosphatase and calcium as well as lymphocyte infiltration in liver and kidney, raising the possibility of liver and kidney toxicity induced by the Ag nanoparticles. Compared with the SiO₂ and Fe₂O₃ nanoparticles showing no systemic distribution in all tissues tested, the Ag concentration in sampled blood and organs in the Ag nanoparticle‐treated group significantly increased with a positive and/or dose‐related trend, meaning that the systemic toxicity of the Ag nanoparticles, including liver and kidney toxicity, might be explained by extensive systemic distribution of Ag originating from the Ag nanoparticles. Our current results suggest that further study is required to identify that Ag detected outside the gastrointestinal tract were indeed a nanoparticle form or ionized form. Copyright © 2015 John Wiley & Sons, Ltd.     

Brain pharmacokinetics and tissue distribution of tetrahydropalmatine enantiomers in rats after oral administration of the racemate

Tetrahydropalmatine (THP), a racemic mixture, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma Corydalis (yanhusuo). The main objective of this study was to determine the brain pharmacokinetics and tissue distribution of THP enantiomers in rats after oral administration of racemic THP (rac-THP). Rats (5 animals/group/per time) were given a single oral dose of rac-THP and killed after different post-treatment times. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured using a validated chiral high performance liquid chromatographic (HPLC) method coupled with an achiral column. The pharmacokinetic profiles of the two enantiomers in six brain regions were significantly different. The peak concentrations (Cmax) and AUC(0-infinity) values of the (-)-enantiomer were significantly greater than the corresponding values for the (+)-enantiomer while the striatum contained the highest peak concentrations compared with the plasma and other brain regions. The tissue distribution studies also revealed significant differences between the two enantiomers in all tissues except the lung. The highest concentrations of both enantiomers were found in the liver. The (-)/(+)-THP ratios in six brain regions and other tissues were consistent with that observed in plasma indicating that the stereoselective disposition of THP in rat brain and other tissues reflects the situation in plasma.     

Comparison of various pharmaceutical preparations of prednicarbate after repeated topical administration to the skin of rats

The following pharmaceutical preparations of prednicarbate (Hoe 777) were tested: fatty ointment 0.1% and 0.25%, ointment 0.1% and 0.25%, cream 0.1% and 0.25%, solution 0.25%. These pharmaceutical preparations were applied 10 times to the shorn back of male Sprague-Dawley rats. After sacrifice the following parameters were recorded: body weight, skin thickness as well as ultimate load, ultimate strain, tensile strength and modulus of elasticity of excised skin strips. Soluble fractions of collagen (soluble in 0.15 and 0.5 molar NaCl solution and in citrate buffer) and insoluble collagen as well as total collagen/g fresh weight were determined. The values of the treated animals were compared with the values of untreated animals and animals treated with the individual base only. As found in earlier studies prednicarbate induced a slight decrease of body weight and skin thickness. Ultimate extension and ultimate load were only barely changed. There was, however, a dose-dependent increase of modulus of elasticity and tensile strength, due to treatment with prednicarbate. Simultaneously, an increase on insoluble collagen and of total collagen per g fresh weight was noted. These results confirm previous findings, indicating a positive correlation between tensile strength and modulus of elasticity of connective tissue with the content of insoluble collagen. The effects of ointment, fatty ointment and cream are very similar, nevertheless, they depend on the type of formulation applied. In the case of prednicarbate solution the dependence of the effects upon the formulation used is very obvious. The increase of tensile strength and modulus of elasticity as well as of insoluble collagen show that very impressively.     

镉对大鼠肾脏和睾丸毒性的比较

大鼠饮水中给镉12wk后,检测了尿低分子蛋白(LMWP)排出量。尿碱性磷酸酶(ALP)活性,血清睾酮水平,睾丸乳酸脱氢酶同功酶(LDH-X)活性,精子计数和形态,雄鼠生育力,肾,睾丸和附睾组织镉含量,并在光镜和电镜下观察上述组织的病理变化,从生化,形态和功能改变三方面比较了大鼠肾脏和睾丸对镉的敏感性,发现尿LMWP和ALP仅在高剂量组显著增加,而血清睾酮和睾丸LDH-X在中剂量纽和低剂量纽已明显降低,说明镉对睾丸的有害作用可出现在肾脏之前。     

Metallothionein-null and wild-type mice show similar cadmium absorption and tissue distribution following oral cadmium administration

Cadmium (Cd) is an environmental pollutant and is toxic to many tissues. Food is the primary source of Cd exposure for the general population. Metallothionein (MT), a cysteine-rich, Cd-binding protein, plays an important role in Cd detoxication. However, the role of MT in Cd absorption and distribution is still controversial. For example, some reports assert that MT in the intestine decreases Cd absorption and increases its distribution to the kidney, relative to the liver. Therefore, to further clarify the role of MT in Cd absorption and tissue distribution, MT-I/II knockout (MT-null) mice and their parental background wild-type mice were given a single dose of (109)Cd (1-300 micromol/kg po or 0.1-30 micromol/kg iv). Cd content in 15 organs was determined 4 h after Cd administration by gamma scintillation spectrometry. Approximately 60% of the Cd administered iv was retained in liver, and about 5% was retained in kidney in both MT-null and wild-type mice. The distribution of iv administered Cd was independent of dose. In contrast, when administered po, approximately 0.15% of the lowest dose (1 micromol/kg) and 0.75% of the highest dose (300 micromol/kg) was detected in the liver of both MT-null and wild-type mice. Similarly in kidney, approximately 0.05% of the dose was detected after the lowest dose and about 0.15% after the higher doses in both MT-null and wild-type mice. In summary, this study demonstrates that the absorption and initial distribution of orally administered Cd is dose dependent but is not influenced by MT.     

Binding of cadmium and mercury by metallothionein in the kidneys and liver of rats following repeated administration

Rats were injected subcutaneously with either cadmium chloride (0.5 mg Cd/kg) or mercuric chloride (0.5 and 0.25 mg Hg/kg) every other day over a period of 6 to 7 weeks. Levels of metals and metallothionein were determined in liver and kidneys. Both cadmium and metallothionein accumulated in these organs during the period of exposure. Mercury and metallothionein accumulated only in the kidneys. Mercury did not accumulate in the liver, nor did it cause an increase of metallothionein in the liver. The molar ratio of 1.6 (metal to metallothionein) in liver was constant for cadmium. In the kidneys this ratio varied from 1 to 3 for both metals, depending on the level of the metal; This ratio was 0.1 for liver mercury.This work was partly supported by the Polish-American agreement No. 05-009-2 with National Institute for Occupational Safety and Health, PHS, USA.