The urinary excretion of epidermal growth factor in the rat is reduced by aprotinin, a proteinase inhibitor.

The present study on the rat shows that i.v. administration of the proteinase inhibitor aprotinin reduces the urinary output of immunoreactive epidermal growth factor (EGF) while the amount of immunoreactive EGF in the kidneys is increased. This indicates that the EGF-precursor in the rat kidney in vivo is processed by an aprotinin inhibitable proteinase. EGF is produced in the kidneys as a precursor with a molecular weight of approximately 130 kDa. In rat urine, nanomolar amounts of 6 kDa EGF are excreted per 24 h together with small amounts of high molecular weight forms of EGF. During i.v. administration of aprotinin the median urinary output of immunoreactive EGF is reduced to 15% of the excretion of control rats (23 pmol/2 h versus 157 pmol/2 h, P less than 0.001). Especially the excretion of 6 kDa EGF is reduced (median excretion 12 pmol/2 h versus 134 pmol/2 h, P less than 0.001). The amount of immunoreactive EGF in the kidney tissue is increased after aprotinin administration (median amount 0.11 pmol EGF/mg protein versus less than 0.04 pmol EGF/mg protein, P less than 0.001). Neither the creatinine clearance, the total urinary protein output, nor the volume of urine produced was affected by aprotinin.     

Intestinal absorption and metabolism of retinoyl beta-glucuronide in humans, and of 15-[14C]-retinoyl beta-glucuronide in rats of different vitamin A status

In order to prove the hypothesis that humans and animals with adequate vitamin A status do not absorb and metabolize orally administered all-trans retinoyl β-glucuronide, unlabeled retinoyl glucuronide (0.1 mmol) was orally dosed to fasting well-nourished young men. Neither retinoyl glucuronide nor retinoic acid, a possible metabolite, appeared in the blood within 12 h after ingestion. Next, radiolabeled all-trans 15-[¹⁴C]-retinoyl β-glucuronide was chemically synthesized by a new procedure, and fed orally to rats of different vitamin A status. Analysis of blood and other tissues 5 or 24 h after the dose, showed the presence of radioactivity ( 0.5%) in the blood of vitamin A deficient rats, but not in sufficient rats. Livers of all rats contained small, but detectable amounts (0.3 to 1.1% of the dose) of radioactivity. The accumulation of radioactivity in the liver was highest in deficient rats. Analysis of the retinoids showed that the radioactivity in serum and liver was due to retinoic acid formed from retinoyl glucuronide. Within 24 h after the dose, 31 to 40% of the administered radioactivity was excreted in the feces, and 2 to 4.7% of the dose was excreted in the urine. Results of the present studies show that oral administration of retinoyl β-glucuronide did not give rise to detectable changes in blood retinoyl glucuronide and/or retinoic acid concentrations in humans or rats with adequate vitamin A status.     

In vivo disposition and stability of DNA frayed wires in mice

DNA frayed wires (DNA_FW) are an alternate form of DNA organization formed by the self-association of several strands of guanine-rich oligonucleotides. The purpose of this study was to define for the first time the blood clearance kinetics, tissue distribution, and stability of DNA_FW in vivo in mice. Single bolus doses (1200 pmol/mouse) of ³²P-DNA_FW and ³²P-random DNA were administered intravenously (IV) and intraperitoneally (IP) followed by scheduled blood, urine, fecal and tissue samplings. Blood clearance kinetics was described well by a first order two-compartment open model. The overall half-lives of elimination from the central compartment (T_1/2)_K10 were 3.57 ± 0.1 h for IV and 2.38 ± 0.11 h for IP. In contrast, random DNA was completely degraded after 15 min regardless of the route of administration. Tissue distribution results demonstrated that DNA_FW were primarily distributed and retained in the liver, intestines, kidneys, and heart. Low levels could also be detected in brain. Autoradiographs of blood, tissues, feces and urine extracts established that DNA_FW remained intact after administration as no measurable levels of metabolites or degradation products were found after 24 h. ³²P-DNA_FW was primarily eliminated via hepato-biliary excretion into feces after either IV or IP administration (51.8 ± 4.53% and 36.2 ± 3.4%, respectively). The improved stability and longer half-life of DNA_FW, previously shown in vitro, is also seen in vivo, indicating that DNA_FW may provide a stable delivery system for DNA gene therapies. In conclusion, this is the first study demonstrating the in vivo stability, pharmacokinetics, and disposition of DNA superstructures.     

Effect of acute administration of mercuric chloride on the disposition of copper, zinc, and iron in the rat

The present study was designed to investigate the effect of mercuric chloride administration on copper, zinc, and iron concentrations in the liver, kidney, lung, heart, spleen, and muscle of rats. The results showed that after dose and time exposure to mercuric chloride, the concentration of mercury in the six tissues was significantly elevated. Data showed that there were no interaction between mercury and tissue iron. There was a considerable elevation of the content of copper in the kidney and liver. The most significant changes in the copper concentration took place in the kidneys. About a twofold increase in the copper content of the kidney was noted after exposure to mercuric chloride (3 mg and 5 mg/kg). Only slight elevations in the copper content occurred in the liver, especially in high dose and longer exposure time. In the remaining organs, the copper content was not changed significantly (p>0.05). The most significant changes in the zinc concentration took place in liver, kidney, lung, and heart (5 mg/kg). Marked changes in kidney zinc concentrations were observed at any of the specified doses. Zinc concentrations were significantly increased in kidney of rats sacrificed 9–48 h after sc injection of HgCl₂ (5 mg/kg); in liver obtained from rats at 18, 24, or 48 h after injection; and in lung after 24 or 48 h of treatment. The heart and spleen zinc concentrations were elevated at 24 and 48 h after injection of HgCl₂ (5 mg/kg), respectively. The results of this study implicate that effects on copper and zinc concentrations of the target tissues of mercury may play an important role in the pathogenesis of acute mercuric chloride intoxication.     

Differences in neurotoxic effects of ochratoxin A, ochracin and ochratoxin-alpha in vitro.

The mycotoxin ochratoxin A (OTA) is a chlorinated dihydroisocoumarin derivative connected through an amide-bond to L-phenylalanine. In a previous study we could show that competition with L-phenylalanine-dependent processes does not play a role in OTA neurotoxicity. To test whether the isocoumarin part is responsible for the neurotoxic effects, we determined in the present study the effects of the hydrolysis product of OTA, ochratoxin-alpha (OTalpha), and of ochracin on embryonic chick brain cell cultures. In addition, we investigated the interaction between OTA and ochracin regarding the neurotoxic effects. We report here that OTalpha did not affect brain cell cultures at concentrations up to 15 microM. With the exception of a small (20%) but significant reduction in cell culture, cellular protein at concentrations above 0.3 microM, in our cell cultures' cell function, as defined by neutral red uptake and MTT-dehydrogenase activity, was only reduced by high OTalpha concentrations (1 mM). Addition of 0.1 microM OTA increased ochracin cytotoxicity as defined by latter parameters. No effects on cell culture NF68kD content could be detected. The results are discussed with regard to the existence of an OTA target interaction binding site.     

Tissue distribution,metabolism, and elimination of perfluorooctanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1-¹⁴C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 μmol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA-derived ¹⁴C was observed. Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered ¹⁴C in the urine. The sex-related difference in urinary elimination resulted in the observed difference in the whole-body elimination half-life (t_1/2) of PFOA in males (t_1/2 = 15 days) and females (t_1/2 < 1 day). Analysis of PFOA-derived ¹⁴C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6-hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA-containing lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA-glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.     

Absorption and metabolism of 4-hydroxyderricin and xanthoangelol after oral administration of Angelica keiskei (Ashitaba) extract in mice

To investigate the absorption and metabolism of 4-hydroxyderricin and xanthoangelol, we established an analytical method based on liquid chromatography-tandem mass spectrometry and measured these compounds in the plasma, urine, feces, liver, kidney, spleen, muscle and white adipose tissues of mice orally administered with Ashitaba extract (50-500mg/kg body weight). 4-Hydroxyderricin and xanthoangelol were quickly absorbed into the plasma, with time-to-maximum plasma concentrations of 2 and 0.5h for 4-hydroxyderricin and xanthoangelol, respectively. Although these compounds have similar structures, the total plasma concentration of 4-hydroxyderricin and its metabolites was approximately 4-fold greater than that of xanthoangelol and its metabolites at 24h. 4-Hydroxyderricin and xanthoangelol were mostly excreted in their aglycone forms and related metabolites (glucuronate and/or sulfate forms) in urine between 2 and 4h after oral administration of Ashitaba extract. On the other hand, these compounds were only excreted in their aglycone forms in feces. When tissue distribution of 4-hydroxyderricin and xanthoangelol was estimated 2h after administration of Ashitaba extract, both compounds were detected in all of the tissues assessed, mainly in their aglycone forms, except in the mesenteric adipose tissue. These results suggest that 4-hydroxyderricin and xanthoangelol are rapidly absorbed and distributed to various tissues.     

Plasma kinetics and urine profile of ethyl glucosides after oral administration in the rat

In this in vivo study, the time course of plasma concentration and the urinary excretion of ethyl alpha-D-glucoside (alpha-EG) and ethyl beta-D-glucoside (beta-EG) were investigated in rats after a single oral dose of 4 mmol/kg body weight. Maximal plasma concentrations of both alpha-EG and beta-EG (EGs) reached approximately 3 mM at 1 h after oral administration and then decreased rapidly. Approximately 80% of EGs administered were excreted into the urine during the first 6 h. Within 24 h, cumulative urinary alpha-EG and beta-EG excretions were estimated to be 87.2+/-7.9% and 85.4+/-5.0%, respectively. Traces of both EGs were detected in plasma and urine 24 h after oral ingestion. The results of this study indicate that almost all of both EGs was rapidly absorbed into the blood stream and easily excreted into the urine after oral administration, and that a small amount of them remained in the rat body 24 h after administration.     

Colorimetric analysis with N,N-dimethyl-p-phenylenediamine of the uptake of intravenously injected horseradish peroxidase by various tissues of the rat

1. A method is described for the colorimetric determination of peroxidase with N,N-dimethyl-p-phenylenediamine. The amount of red pigment formed by peroxidase is proportional to the concentration of enzyme and to the time of incubation during the first 40 to 90 seconds. The influence of the concentration of enzyme, N,N-dimethyl-p-phenylenediamine, H(2)O(2), the time of incubation, pH, the temperature, and the possible interference by oxidizing and reducing agents of tissues has been tested. 2. The method has been used to follow the uptake of intravenously injected horseradish peroxidase by 18 different tissues of the rat over a period of 30 hours. The highest concentration of the injected tracer enzyme was found in extracts of kidney, liver, bone marrow, thymus, and spleen. Considerable amounts were taken up by pancreas, prostate, epididymis, and small intestine. Lower concentrations were found in extracts of lung, stomach, heart, and skeletal muscle, aorta, skin, and connective tissue. No uptake was observed by brain and peripheral nerve tissue. 3. Tissue homogenates containing high concentrations of the injected peroxidase, in general also showed high or average activity of acid phosphatase. 4. Six hours after intravenous administration, the liver contained 27 per cent, the kidney 12 per cent, and the spleen, 1.4 per cent of the injected dose. 5. Approximately 20 per cent of the injected peroxidase was excreted in the urine during the first 6 hours, and the concentration of peroxidase in blood serum and urine fell exponentially during this time. After 6 hours, only low concentrations were excreted in the urine but low enzyme activity was still detectable after 30 hours. Approximately 6 per cent of the injected dose was excreted in the feces from 6 to 20 hours after administration. 6. After feeding through a stomach tube, low concentrations of peroxidase were found in blood serum and urine. Considerable variations in the extent of absorption from the gastrointestinal tract were observed in individual rats.     

Tissue distribution and antithrombotic activity of unlabeled or 14C-labeled porcine intestinal mucosal heparin following administration to rats by the oral route

Distribution and antithrombotic activity of orally administered unfractionated porcine heparin were studied. [14C]Heparin was prepared by de-N-acetylation of porcine mucosal heparin followed by re-N-acetylation, using [14C]acetic anhydride. [14C]Heparin and (or) cold heparin (60 mg/kg) were administered by stomach tube to male Wistar rats. Blood, all levels of gut and gut contents, liver, lung, spleen, kidney, and aortic and vena caval endothelium were collected under deep anesthesia at 3, 6, 15, 30, and 60 min and 4 and 24 h (6 rats/group) after administration. Urine and feces were collected at 24 h, using metabolic cages. In three additional rats, drugs were administered in gelatin capsules. Tissues listed above and tongue, esophagus, trachea, brain, heart, thymus, bile ducts, vena caval and aortic walls, ureters, bladder, samples of muscle, skin, hair, and bone marrow were collected at 24 h. Radioactivity and chemical heparin, measured by agarose gel electrophoresis, were observed in all tissues examined as well as gut washes, plasma, urine, and feces. Radiolabel recovered was confirmed to be heparin by autoradiograms of gradient polyacrylamide electrophoretic gels. [14C]Heparin and chemical heparin in gut tissue suggest a transit time of 4 h. Porcine or bovine heparin (7.5 mg/kg), administered by stomach tube, decreased the incidence of thrombosis induced by applying 10% formalin in 65% methanol to the exposed jugular vein of rats. Heparin isolation from non-gut tissue, endothelium, urine, and plasma and the observed antithrombotic effect are consistent with oral bioavailability.     

Gas-liquid chromatographic determination of the distribution of 3,3',4,4'-tetrachlorobiphenyl in the adult female rat following short-term oral administration

A gas-liquid chromatographic assay using electron-capture detection was developed for the quantitation of 3,3',4,4'-tetrachlorobiphenyl (TCBP) in the serum, urine, brain, liver, adipose tissue, and feces of the rat. The sample preparation involves extraction of 3,3',4,4'-TCBP with hexane under neutral or alkaline conditions (and washing with concentrated acid for feces only). Aqueous standards are used for calibration of the assay, except for adipose tissue. The lower limit of quantitative sensitivity of the assay for 3,3',4,4'-TCBP is 25 ng/mL for serum and urine and 125 ng/g for brain, liver, adipose tissue, and feces, which can be extended to 5 ng/mL and 25 ng/g, respectively, by analyzing a larger aliquot of the hexane extract. The overall accuracy is greater than 95% for serum, urine, brain and feces and 86% for liver, and the within-day coefficient of variation does not exceed 8.6%. 3,3',4,4'-TCBP was administered orally to adult, female, Sprague-Dawley rats in the dosage regimens: 0.2, 0.5 and 2 mg X kg-1 X day-1 for 10 days and 5 mg X kg-1 X day-1 for 4 days. 3,3',4,4'-TCBP distributed preferentially into adipose tissue and liver, where the xenobiotic concentration was greater in adipose tissue. The adipose tissue and hepatic 3,3',4,4'-TCBP concentrations were dependent on both the absolute dose and dosing schedule of the xenobiotic. Only trace concentrations, usually below the lower limit of quantitation, were detected in the serum, brain and kidney. Fecal excretion of 3,3',4,4'-TCBP was greater than urinary excretion for the 5 mg X kg-1 X day-1 X 4-day regimen.     

Metabolism of echitamine and plumbagin in rats

When administered to rats, echitamine was absorbed rapidly from the tissues and was detected in circulation within 30 min. The drug level reached a maximum value by 2 h and then decreased steadily. The drug had completely disappeared from the blood in 6 h. The presence of echitamine was observed within 2 h in urine and the maximum amount of drug was excreted between 2 and 4 h. About 90% of the drug was excreted in urine in 24 h and the drug could not be detected in urine after 48 h. Along with echitamine, its metabolites were also detected in the urine. Plumbagin was not detected in blood upto 24 h when administered into rats. The drug was detected in urine within 4 h after administration; a major portion of the drug was excreted in urine by 24 h and traces of the drug were observed in the urine even after 48 h.     

Metabolism of ochratoxin A by rats.

Albino rats were given ochratoxin A (6.6 mg/kg body weight) intraperitoneally or per os. Independent of route administration, 6% of a given dose was excreted as the toxin, 1 to 1.5% as (4R)-4-hydroxyochratoxin A, and 25 to 27% as ochratoxin alpha in the urine. The metabolite (4S)-4-hydroxyochratoxin A, which is formed by rat liver microsomes in the presence of NADPH, was not detected. Only traces of ochratoxins A and alpha were found in feces. Identical experiments were carried out with brown rats, since the Km value for the formation of the 4S epimer was considerably lower when brown rat microsomes were used. About the same ratios of metabolites and metabolite recoveries as those found for albino rats were found for brown rats. Brown rats were also given the two hydroxylated metabolites and ochratoxin alpha (0.66 mg/kg body weight) intraperitoneally. The three compounds were excreted in the urine; within 48 h, 90% recovery of ochratoxin alpha and 54 and 35%, respectively, of the 4R and 4S isomers were observed.     

根田鼠气味识别的性二型

以新鲜尿和粪作气味源,在行为选择箱中观察根田鼠的行为识别模式,结果表明：雌鼠对陌生同性尿、粪气味源行为识别的差异不显,雄鼠对陌生同性尿、粪气味源的行为识别在多个指标上存在显差异;根田鼠对陌生异性尿、粪的行为响应模式无明显差异;除嗅舔时间外,雌、雄鼠对粪气味的行为识别在其他指标上不存在明显差异;比较雌、雄鼠对尿刺激的行为识别发现,雄鼠对尿刺激的访问频次和反标记显大于雌鼠,雌性嗅舔时间显大于雄性,其他方面二之间并无显差异。因此,雌、雄性根田鼠对粪气味的行为识别模式不存在性别差异;对尿气味的行为识别模式存在性别差异。     

Pharmacokinetics, tissue distribution and excretion study of dl-praeruptorin A of Peucedanum praeruptorum in rats by liquid chromatography tandem mass spectrometry

dl-Praeruptorin A (Pd-Ia), isolated from Chinese traditional herbal medicine Peucedanum praeruptorum Dunn, has been proved to be a novel Ca²⁺-influx blocker and K⁺-channel opener, and displayed bright prospects in prevention and therapy of cardiac diseases. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of Pd-Ia in rats following a single intravenous (i.v.) administration. The levels of Pd-Ia in plasma, tissues, bile, urine and feces were measured by a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that Pd-Ia was rapidly distributed and then eliminated from rat plasma and manifested linear dynamics in dose range of 5-20 mg/kg. The mean elimination half-life (t_1/2) of Pd-Ia for 5, 10 and 20 mg/kg dose were 57.46, 60.87 and 59.01 min, respectively. The major distribution tissues of Pd-Ia in rats were spleen, heart and lung, and low polarity enabled Pd-Ia to cross the blood-brain barrier. There was no long-term accumulation of Pd-Ia in rat tissues. Total recoveries of Pd-Ia within 24 h were low (0.097% in bile, 0.120% in urine and 0.009% in feces), which might be resulted from liver first pass effect.     

Synthesis and pharmacokinetics of strontium fructose 1,6-diphosphate (Sr-FDP) as a potential anti-osteoporosis agent in intact and ovariectomized rats

A novel strontium compound has been synthesized by the reaction of fructose-1,6-diphosphate with strontium (Sr-FDP). The compound was characterized and confirmed with elemental analyses and spectroscopic (IR, NMR) methods. The pharmacokinetic profiles of Sr-FDP were investigated in Sprague-Dawley rats following oral administration at a dose of 110, 220, and 440 mg/kg respectively. Pharmacokinetic differences were also compared in intact rats and ovariectomized rats with and without estrogen supplement. Strontium concentrations in plasma, urine, tissue and feces were determined by graphite furnace atomic absorption spectroscopy (GFAAS). The results showed that Sr-FDP was absorbed rapidly with T_max < 1 h in all the groups with AUC_0-∞ proportional to the oral dose. The pharmacokinetic profiles were characterized by long half-life, a large apparent volume of distribution. The highest Sr concentration was observed in the bone at 6 h, and the level of Sr decreased close to the baseline in heart, liver, spleen, lung, intestine, brain and kidney after 12 h. The cumulative amounts of Sr over 96 h were found to be ~ 3% in urine, but ~ 70% in feces suggesting that the parent drug was mainly excreted from the intestine. The C_max and AUC_0-∞ of Sr-FDP in ovariectomized rats were significantly decreased compared to those in intact rats, and this trend was ameliorated by using 17-beta-estradiol (E₂) treatment in the ovariectomized rats.     

Effect of sex and time of sampling on selenium and glutathione peroxidase activity in tissues of mature rats

Sprague-Dawley rats were used to investigate variations in measures of glutathione peroxidase (GSH-Px) and selenium (Se) concentration resulting from diurnal cycles and sex. Mature rats (equal numbers of males and females) were killed at 4 h intervals over a 48 h period (0200, 0600, 1000, 1800 and 2200 h each day). Selenium and GSH-Px were measured in plasma, erythrocytes, and liver and kidney cytosols. Selenium concentrations did not vary diurnally, but plasma GSH-Px activities were higher during the light than dark periods. Males had greater plasma GSH-Px activities and Se concentrations (42 EU and .45 mg/kg, respectively) than females (35 EU and .41 mg/kg respectively). GSH-Px activities were also higher in male kidney cytosols than females (117 and 76 EU, respectively). Selenium and GSH-Px activities, however, were lower in male liver cytosols (.48 mg/kg and 272 EU) than females (1.19 mg/kg and 795 EU, respectively). These data suggest that Se is distributed differently in male and female rats and the difference in Se distribution is accomplished by differences in GSH-Px activities.     

Pharmacokinetic and tissue distribution study of [14C]fluasterone in male Beagle dogs following intravenous,oral and subcutaneous dosing routes

The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [¹⁴C]fluasterone following intravenous (iv), subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [¹⁴C]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t_max; however, the observed C_max following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC_0–∞). Tissue distribution analysis 2 h post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24 h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24 h.     

Metabolism of stevioside by healthy subjects

Stevioside (250-mg capsules) was given thrice daily for 3 days to 10 healthy subjects. Blood samples were collected and blood pressure measured after nocturnal fasting, before and at different time points during the third day of the administration of stevioside. No significant differences were found between the control and the stevioside condition for blood pressure and blood biochemical parameters. The 24-hr urinary volume and urinary excretion of electrolytes were not significantly different. Likewise, no significant difference was found for mean blood glucose and insulin between control and stevioside conditions. Thus, oral stevioside is not directly effective as a hypotensive or hypoglycemic agent in healthy subjects at the dose administered in this study. Stevioside, free steviol, and steviol metabolites were analyzed in blood, feces, and urine after 3 days of stevioside administration. No uptake was found of stevioside by the gastrointestinal tract or the amounts taken up were very low and below the detection limit of the UV detector. Stomach juice did not degrade stevioside. All the stevioside reaching the colon was degraded by micro-organisms into steviol, the only metabolite found in feces. In blood plasma, no stevioside, no free steviol or other free steviol metabolites were found. However, steviol glucuronide (SV glu) was found in maximum concentrations of 33 micro g/ml (21.3 micro g steviol equivalents/ml). In urine, no stevioside or free steviol were present, but SV glu was found in amounts of up to 318 mg/24-hr urine (205 mg steviol equivalents/24 hrs). No other steviol derivatives were detected. In feces, besides free steviol, no other steviol metabolites or conjugates were detected. Steviol was excreted as SV glu in urine.     

Comparative Excretion and Tissue Distribution of Selenium in Mice and Rats Following Treatment with Diphenyl Diselenide

The purpose of this study was to provide data about in vivo tissue distribution and excretion of diphenyl diselenide ((PhSe)₂) in rats and mice through determination of selenium levels in different biological samples. (PhSe)₂ (500?mg/kg, dissolved in canola oil) was administered to animals once a day per oral. After this, mice and rats were housed in metabolic cages (one animal per cage) and urine and feces were collected at specific times after treatment. Three to five animals per group (for each time-point) were anesthetized and blood samples were collected at 0 and 30?min, 24?h, at day 5, 15, and 30 after (PhSe)₂ administration. The plasma and red blood cells were separated. Brain, liver, lungs, kidneys, and adipose tissue were also collected. The determination of selenium levels was performed by inductively coupled plasma atomic emission spectrometry. The main results indicate that: (1) urine is an important route of excretion of selenium originated from (PhSe)₂ in mice and rats; (2) a large amount of (PhSe)₂ or some of its metabolites are stored in fat; (3) the content of selenium found in plasma was low; and (4) liver and kidneys are the tissues with high amounts of selenium.