Biomedical subjects

C Fleck

Publications and source records attributed to C Fleck.

At least 55 records · Page 3Linked to original sources

PubMed1991

Ontogenetic changes in hepatic glutathione system (synthesis, catabolism, export) of male Uje:WIST rats.

The age-courses of concentrations of reduced (GSH) and oxidized (GSSG) glutathione, of GSH synthesizing enzyme activities, of glutathione S-transferase (GST), of GSSG-reductase (GR) and of biliary GSH and GSSG export were measured in livers from male Uje:WIST rats. Additionally, the age-courses of plasma GSH and GSSG concentrations were investigated. The hepatic level of GSH showed a biphasic pattern with a first maximum immediately after birth and a small second peak at the 50th day of life. The GSSG level increased continuously up to day 60 of life. The cytosolic GSH synthesizing enzyme activities showed diverse developmental patterns indicating different regulation principles. The hepatic activity of GR was relatively constant in the different age groups after birth. The GST activity (with o-dinitrobenzene as substrate) was relatively low at birth (about 30% of the maximum measured at day 60 of life). The maximum of GSH plasma level was found at birth. With increasing age a significant decrease in this level was observed. The excretion rate of total GSH (GSH + 2 GSSG) in bile was found to increase about 9-fold between 15 and 105 days of age. The results indicate that changes of hepatic GSH concentration with age are dependent on numerous factors. The balance between synthesis, catabolism and export is important for the maintenance of this level.

Aging↗

PubMed1991

Relation between renal and hepatic excretion of drugs: XV. Organ distribution and transport of the new antiarrhythmic drug Bonnecor in kidney and liver of rats.

Following administration of various doses of 14C-labeled Bonnecor (0.15 to 0.6 mg/100 g b.wt. i.v.) renal excretion of 14C-radioactivity dominates and the total rate of excretion both via kidney and liver reaches 60% during 6 h clearance experiment, independent of the administered dose. Otherwise nearly the same concentration of 14C-radioactivity can be measured in kidney and liver tissue. An alpha- und beta-slope of disappearance from the tissue seems to exist. At different times after administration of Bonnecor (0 to 15 h) the concentrations in kidney and liver tissue are distinctly higher compared with plasma concentrations. In vitro experiments on tissue slices confirm a nearly identical degree of accumulation of 14C-radioactivity in liver and kidney. In renal cortical slices the high degree of accumulation depends on active tubular transport processes. Comparing accumulation in liver slices under aerobic and anaerobic conditions a preferential passive uptake of Bonnecor can be demonstrated. Efflux kinetics in slices from liver and kidney cortex is in accordance with this interpretation.

Animals↗

PubMed1991

[Electron microscopic evidence of aluminum in lysosomes of kidney cells by electron energy loss spectroscopy].

Aluminium effects have increasing attention in long term dialysis of kidney patients and in a number of cerebral diseases. At present, however, there are still many open points concerning its localization and actions in the cell. If using electron spectroscopic imaging (ESI), aluminium could be directly demonstrated in the lysosomes of the kidney cells of uraemic rats experimentally loaded with aluminium. These findings were corroborated by means of electron energy loss spectroscopy (EELS).

Aluminum↗

PubMed1990

[Possibilities for increasing the elimination rate of Bonnecor].

Bonnecor is excreted in rats both via urine (3/4) and bile (1/4). It was the aim of this study to find out suitable methods for detoxication of a poisoning with this antiarrhytmic drug. In vivo methods intended to enhance the renal excretion of Bonnecor (forced diuresis, changes in urinary pH-values, peritoneal dialysis) are not qualified for therapeutically relevant increase of Bonnecor elimination. Relating to this Bonnecor is quite comparable with other antiarrhythmic drugs or dibenzazepine derivatives. The hemoperfusion can be recommended for the therapy of a Bonnecor overdosage as a propping up of symptomatic methods of intensive care, which are precendentally indicated. Therefore the therapy of a Bonnecor poisoning seems to be more promising compared to intoxications with other antiarrhythmics. Among the adsorbents tested, the resin Wofatit UH91 is most suitable to remove Bonnecor from the organism. If hemoperfusion equipments are not available, hemodialysis can also be used for acceleration of Bonnecor elimination, although its effectivity is only one third of that of hemoperfusion.

Animals↗

PubMed1990

Influence of xenobiotics on bile flow and bile composition in rats--methodological approach.

Optimal procedures for the investigation of bile flow and excretion of bile constituents are described, and data are given regarding sex and age dependency, use of narcotic drugs and replacement of water loss in Wistar rats. A combination of ketamine and xylazine can be recommended for anaesthesia. In long time studies saline infusion keeps bile and urine production constant over a period of 6 h. Bile flow and biliary excretion of bile acids and electrolytes are immature at birth and reach a maximum between the 20th and 60th day of life. The biliary excretion of cholesterol decreases with age. The concentrations of bile constituents such as lipids, glutathione, protein, uric acid, urea, osmotically active substances, and steroid hormones are given for adult rats. Bilateral nephrectomy decreases bile flow in mature rats only.

Aging↗

PubMed1990

Age dependent differences in stimulation and compensation of renal and biliary transport processes. Correlation to the physicochemical properties of the exerted substances.

The relation between renal and biliary excretion of drugs was investigated in dependence on physicochemical factors, on age, and on repeated administration of hormones and xenobiotics for stimulation. Furthermore, the relation between molecular parameters of drugs and the degree of compensation of drug elimination after blockade of one excretion pathway (nephrectomy--NX, bile duct ligation--DL) was characterized. Experiments were performed on female 20-day and 55-day-old rats to demonstrate changes in the relationship between kidney and liver for drug elimination during ontogenesis. Finally it was tried to correlate the effect of a stimulation of elimination capacity of kidney and liver after repeated administration of hormones or xenobiotics and the physicochemical features of clearance substances tested. For estimation of physicochemical differences of the model substances a so called "rank coefficient" R (0-100) was used. It was calculated from molecular weight, lipophilicity, degree of ionization at pH 7.4, and protein binding rate. Compounds with low ranks (low values of molecular weight, lipophilicity, and protein binding, nearly completely ionic at pH 7.4) are eliminated first of all via urine. High ranks are typical of drugs preferentially eliminated into bile. Intermediate ranks (40-60) have been obtained for substances eliminated effectively both via kidney and liver. For these compounds only, a distinct compensation via the intact elimination route can be expected after blocking operations. Qualitative age differences could not be found. But there were differences concerning relation between acceleration of transport capacity of kidney and liver during postnatal maturation and physicochemical properties of the respective test substance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1990

Factors determining the relationship between renal and hepatic excretion of xenobiotics.

Relation between kidney and liver in the excretion of drugs depends on the physicochemical properties of each substance tested. The calculations of this relationship are based on a so-called rank coefficient (0-100) calculated from molecular weight, lipophilicity, degree of dissociation under physiological conditions, and protein binding rate. The results of the correlation between one of these physicochemical values and drug elimination were stochastically. Experiments were performed with 9 test substances which were distinctly different concerning their physicochemical features. Substances with a rank coefficient less than 20 (low molecular weight, low lipophilicity, preferentially ionic at pH 7.4) are eliminated effectively via the kidney. Compounds having an intermediate rank coefficient (40-60) were quantitatively excreted into urine as well. For drugs with high ranks greater than 60 (high values of molecular weight, protein binding, and lipophilicity, almost exclusively nonionic), renal excretion can be neglected. Quite inverse relations between ranks and hepatic excretion have been found: low ranks indicate an ineffective secretion of the respective drug into bile. With increasing ranks (40-60), biliary excretion increases and reaches a maximum (approximately 40% of supply). This maximum is caused by limited hepatic blood flow and by the capacity of hepatic uptake carriers. Blockade of one elimination pathway (bilateral nephrectomy or bile duct ligation) is followed by a sufficient compensation of drug excretion via the alternative elimination route only, if the test substance belongs to the intermediate group (ranks between 40 and 60). For substances with high or low ranks a compensation of drug excretion can be excluded.

Animals↗

PubMed1990

[The effect of propranolol (Obsidan) as well as propranolol and fenoterol (Partusisten) on the motility of the smooth uterus musculature in vitro].

Propranolol (1; Obsidan) relaxes in vitro stripes of smooth muscles of non-pregnant rat's uterus in a concentration dependent manner. In contrast, on uterine muscle stripes of pregnant rats 1 causes small contractions. In an combination of 1 and fenoterol (2; Partusisten) (20:1) 1 prevents the relaxing effect of 2, reported to be an inhibitor of uterine muscle activity. This antagonism is most distinct on stripes of pregnant rat's uterus.

Animals↗

PubMed1989

Relation between renal and hepatic excretion of drugs: XIII. Pharmacokinetics of new antiarrhythmic drug Bonnecor in rats with normal and impaired excretory functions.

The clearance of 14C-Bonnecor, a weak organic cation, was measured in anaesthetized rats during 6 h after administration. The drug and its labelled metabolites are excreted both via kidney and liver. The renal excretion dominates especially following high doses. After bile duct ligation the renal excretion of Bonnecor increases significantly whereas in nephrectomized rats the biliary excretion of this substance is distinctly reduced. Plasma protein binding ratios amount to 60-70%. Renal removal of Bonnecor and the formed metabolites is in part a result of glomerular filtration. Increased urinary excretion of 14C-Bonnecor-activity under conditions of forced diuresis indicates the involvement of tubular reabsorption in renal handling of the drug and its metabolites. These in vivo results could be confirmed in experiments on renal cortical slices indicating a distinct tubular transport of the drug and its metabolites. In the kidney the aerobic accumulation of Bonnecor is very effective. Surprisingly, under anaerobic incubation conditions, uptake of Bonnecor into renal tissue remains relatively high indicating a distinct binding of Bonnecor within the tubular cells. In the liver the accumulation of Bonnecor is lower compared to the kidney. Furthermore, enterohepatic circulation of Bonnecor and its metabolites was checked. In animals with intact biliary tract, renal removal of 14C-Bonnecor-activity from the organism is significantly higher than in rats with bile duct cannulation. Reinfusion of bile increased renal excretion of 14C-Bonnecor-activity additionally. Both results indicate an effective intestinal reabsorption and enterohepatic circulation of this drug.

Animals↗

PubMed1989

[Determination of the biliary excretion of reduced and oxidized glutathione].

An enzymatic method is presented for the detection of biliary excretion of reduced (GSH) and oxidized (GSSG) glutathione. The biliary excretion of GSH is 65.63 +/- 7.23 nmoles/kg b.w. x min and of GSSG 5.90 +/- 0.64 nmoles/kg b.w. x min in 55 day-old female rats, respectively. The recovery is 97.39 +/- 0.40% for GSH and 91.05 +/- 2.30% for GSSG. Cysteine which can be detected in bile, does not influence the accuracy of the results.

Animals↗

PubMed1989

Relation between renal and hepatic excretion of drugs. XII. Influence of dexamethasone, triiodothyronine, or phenobarbital on the elimination of sulfonamides in rats of different ages.

Relation between renal and hepatic excretion of sulfonamides depends on their physicochemical properties. So does the effect of treatment with triiodothyronine (T3), dexamethasone, or phenobarbital (PB) on elimination of sulfonamides. After repeated administration of T3, dexamethasone, or PB an intensification of biliary sulfaclomide excretion occurs whereas hepatic transport of sulfisomidine or sulfameracine is not affected. After T3 treatment, bile flow of adult rats with intact kidneys increases by 60%. This increase is connected with enhanced sodium excretion into bile. Renal excretion of the three sulfonamides investigated here seems not to be influenced by different kinds of treatment. However, if the tubular reabsorption within the kidney is diminished by forced diuresis renal sulfaclomide excretion is enhanced after treatment with T3, dexamethasone, or PB. Surprisingly, under these conditions (mannitol diuresis), sulfaclomide excretion via bile reaches only control values and stimulatory effects of all kinds of treatment are suppressed both in young and adult animals with the exception of dexamethasone in adult rats. In young rats treated with T3 or PB there is no additional compensatory increase in sulfaclomide excretion after nephrectomy whereas in adult rats sulfaclomide elimination via bile is significant diminished.

Animals↗

PubMed1989

[The effect of chronic aluminum loading on lysosomal enzymes in serum and organ homogenates. Methodologic aspects].

The influence of aluminium administration both on the lysosomes and on the activity of DNA-dependent enzymes in rats with intact kidney function or following partial nephrectomy was investigated. The elevation in free N-acetyl-beta-D-glucosaminidase in connection with a decrease of latent beta-NAG-level in liver, spleen and kidneys may be supposed a dose dependent aluminium damage of the lysosomes. Moreover, the decrease of free and total beta-glucuronidase in the liver and spleen could be caused by a selective inhibition of synthesis of this enzyme.

Acetylglucosamine↗

PubMed1988

Relation between renal and hepatic excretion of drugs: X. Excretion of nalorphine in young and adult rats pretreated with hormones or xenobiotics.

Different processes are involved in renal and hepatic excretion of organic anions and cations. In contrast to our knowledge of anion excretion, information about cation transport in kidney and liver is relatively scarce. In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.

Aging↗

PubMed1988

Relation between renal and hepatic excretion in drugs. VIII. Influence of triiodothyronine on maturation of phenol red excretion in rats.

Experiments were performed on 10-, 20-, and 55-day-old female rats. Administration of triiodothyronine (T3; 10 or 20 micrograms/100 g b.wt. for 3 days, once daily) was followed by a significant increase in renal phenol red excretion in 20-day-old and older rats. In 10-day-old rats there was no stimulatory effect of T3 on renal excretion of the dye. On the other hand, biliary excretion of phenol red was significantly diminished in all age groups. Surprisingly, in nephrectomized rats there was a significant increase in hepatic dye excretion in 20- and 55-day-old rats after T3. This increase in transport capacity via liver was connected with a distinct rise of bile flow. In experiments on tissue slices phenol red accumulation was investigated at different medium concentrations. In renal cortical slices there was no significant influence of T3 on specific accumulation of phenol red per 1 g organ wet weight, whereas aerobic accumulation of the dye seems to be diminished in liver tissue after T3 treatment. But in all age groups kidney weight increased significantly. Calculation of total accumulation (= specific accumulation x organ wet weight) resulted in a significantly enhanced renal transport capacity for phenol red in all age groups. In contrast, total hepatic accumulation was reduced independently of age.

Aging↗

PubMed1988

Relation between renal and hepatic excretion of drugs: VII. Hepatic and renal excretion of phenol red in thioacetamide-induced acute and chronic liver damage.

Acute and chronic liver damage was induced in rats by thioacetamide (TAA). Centrilobular liver cell damage associated with an accumulation of lipid droplets was produced by a single high dose (10 mg TAA/100 g b.m.). Liver fibrosis, micronodular and macronodular liver cirrhosis were induced by chronic TAA treatment (300 ml/l drinking water for 1.5, 3 or 6 months). Acute administration of TAA caused a significant decrease of hepatic phenol red excretion but no compensatory increase of its urinary excretion. In contrast, 24 h after bile duct ligation renal excretion of the dye increased by about 50%. After chronic exposure to TAA for three months hepatic phenol red excretion remained reduced and renal excretion raised significantly. This compensatory increase of urinary excreted phenol red amounts did not occur after 6 months of TAA treatment, probably as a result of additional nephrotoxicity of TAA. Two weeks after cessation of TAA exposure for 3 months, hepatic and renal phenol red excretion returned to normal. Bile flow per animal increased significantly after 3 months of TAA exposure. Apparently this is due to a reduced intrahepatic reabsorption of canalicular bile in TAA-damaged liver.

Animals↗

PubMed1988

Relation between renal and hepatic excretion of drugs: IX. Acceleration of phenol red excretion via kidney and liver in rats of different ages by dexamethasone treatment.

Experiments were performed on 10-, 20-, and 55-day-old female rats. After treatment with dexamethasone (60 or 80 micrograms/100 g b.wt. for 3 days, once daily) there is a significant increase in renal phenol red excretion only in 10-day-old rats. In contrast, the stimulatory effect of dexamethasone treatment on the hepatic excretion of this dye occurs exclusively in mature, 55-day-old rats. After repeated administration of this hormone in nephrectomized rats there is an increase of hepatic phenol red excretion, and maximal transport capacity increases from 6-8 to 12 mg/100g b.wt. X hour. In renal cortical slices there is no significant influence of dexamethasone on phenol red accumulation in vitro, whereas accumulation of the dye in liver tissue seems to be diminished. In rats of all groups kidney and liver weights increased significantly after dexamethasone treatment. Calculation of total accumulation capacity (= accumulation per 1 g X organ wet weight) also results in unchanged accumulation capacity in the kidney, but transported phenol red amounts in the liver are distinctly diminished. This is in contrast to the in vivo findings. Possible reasons are discussed.

Aging↗

PubMed1988

Relation between renal and hepatic excretion of drugs. XI. Excretion of sulfonamides with various physico-chemical properties of different ages--influence of nephrectomy or bile duct ligation.

The pharmacokinetics of a series of 6-sulfonamides, with gradually increasing molecular weights, were studied in anaesthetized rats after intravenous bolus injection. Immature (20-day-old) and adult (55-day-old) rats were compared. In both age groups renal excretion of all sulfonamides tested here dominates (about 5- to 10-fold). In 20-day-old rats renal and hepatic excretions are immature and reach about 50% (liver) or 30% (kidney) of adult values. Relation between renal and hepatic excretion of sulfonamides is strongly correlated to the lipophilicity of these substances. Hepatic excretion of sulfonamides seems to be correlated to their pKa-values. Concerning their excretion via urine it is necessary to correlate different steps of renal transport to physico-chemical properties in detail. A general correlation between renal excretion of sulfonamides and their chemical structure obviously does not exist. After bile duct ligation 24 h before clearance experiments no compensatory increase of renal sulfonamide excretion occurs. 24 h following bilateral nephrectomy hepatic excretion of sulfonamides is significantly enhanced; however, this phenomenon is related to physico-chemical properties of the sulfonamides. Age differences in compensation of one elimination pathway do not exist.

Aging↗

PubMed1988

Inhibition of kidney function after blockade of thromboxane synthetase by imidazole in anaesthetized rats.

Experiments on anaesthetized female Wistar rats have shown that imidazole reduces renal excretion of p-aminohippurate (PAH). This effect occurs only after administration of imidazole simultaneously with a volume load (2 ml/100 g b.wt.). Injection of imidazole immediately before a PAH bolus (100 mg/100 g b.wt. in 2 ml) is followed by reduced PAH excretion via urine for at least 1 hour. In contrast, if a PAH bolus is given 20 min or later after imidazole no effect of this drug on renal PAH transport is demonstrable. These findings indicate that imidazole can interfere effectively with thromboxane synthesis only if thromboxane production is activated by volume expansion. Interestingly, despite 40% reduction of renal PAH excretion in volumen loaded rats, PAH serum disappearance is identical in controls and imidazole treated rats. Thus differences in the volume of distribution for PAH after imidazole must be expected. Under our experimental conditions imidazole was without effect on renal electrolyte excretion.

Animals↗