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At least 865 records · Page 48Linked to original sources

PubMed2004

Tissue distribution, stability, and pharmacokinetics of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in human colon carcinoma COLO205 tumor-bearing nude mice.

Apo2L/TRAIL [Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand], a member of the TNF cytokine superfamily, induces cell death by apoptosis in a number of human cancer cells and is a potential agent for cancer therapy. We have characterized the in vitro stability of Apo2L/TRAIL in human serum and the tissue distribution and metabolism of Apo2L/TRAIL in a xenograft model of human colon carcinoma (COLO205). Apo2L/TRAIL was stable after incubation in human serum, with no significant high molecular weight complexes or degradation products observed. After i.v. administration of 125I-Apo2L/TRAIL to mice, a small percentage of the radiolabeled drug was seen as high molecular weight complex or as low molecular weight degradation products in plasma. However, the most abundant radioactive species corresponded to the intact Apo2L/TRAIL monomer, indicative of the relative stability of this recombinant protein in blood. Distribution of 125I-Apo2L/TRAIL to organs and solid xenograft tumors was limited. Intact 125I-Apo2L/TRAIL was detectable in the solid tumor at all time points and was the only tissue in which radioactivity transiently increased over time. Kidney contained the highest levels of radioactivity. Radioactive signal reached a tissue-to-blood ratio of 18 in the kidney cortex region when 125I-Apo2L/TRAIL was given in the presence of excess unlabeled ligand. In contrast to blood, extensive 125I-Apo2L/TRAIL degradation was observed in the kidney and, to a lesser degree, in the solid tumor and other organs, including liver, spleen, and lung. Our studies demonstrated that Apo2L/TRAIL is stable in the circulation, localizes to human solid xenograft tumors, and is primarily eliminated through the kidney.

Animals↗

PubMed1979

Tissue distribution of paraquat and diquat after oral administration in rats.

The differential distribution of paraquat and diquat in liver, kidney, lung, brain and heart has been studied after oral administration of the LD50 or LD50/2 to rats. Paraquat concentrations were highest in all organs at 24 hours; at this time concentrations in kidney and lung were 2 to 3 times higher than at 2 hours. In contrast, with the exception of kidney, tissue diquat concentrations were highest at 2 hours. There was severe lung damage at 24 hours after paraquat; diquat aid not produce severe lung lesions, but caused intestinal distention and diarrhea. These findings suggest that the difference in the toxicity of paraquat and diquat is related to their difference in tissue distribution and excretion.

Animals↗

PubMed1982

In vivo clearance and tissue distribution of C5a and C5a des arginine complement fragments in rabbits.

We have previously shown a marked difference in the inflammatory response to human C5a or C5a des arginine (Arg) instilled in rabbit lungs. These studies raised the question of where C5a and C5a des Arg are processes in vivo and what role neutrophils may play in the tissue distribution of these two mediators. After intravenous injection of purified, biologically active 125I-C5a or 125I-C5a des Arg, adult rabbits were serially bled and then killed at various time intervals. Although greater than 50% of the injected radioactivity was cleared from the circulation within 2 min for both mediators, C5a des Arg persisted in the circulation longer than C5a. C5a instillation caused an acute neutropenia, whereas C5a des Arg caused a less severe and more prolonged neutropenia, preceding a neutrophilic response observed with both mediators. Clearance of the mediators was primarily seen in the highly vascularized organs: the lung, spleen, liver, and kidney. A time-dependent accumulation was seen initially in the lung, followed by the spleen, liver, and kidney. Histologic examination showed a marked increase in the number of neutrophils within the lung and spleen. Depletion of circulating neutrophils by nitrogen mustard pretreatment of rabbits showed no change in the amount of labeled mediator bound in the lung, whereas splenic accumulation was dependent on the presence of neutrophils. These results indicate that C5a and C5a des Arg are rapidly removed from the circulation by specific accumulation in vascularized tissues. Clearance by the lung was not affected by neutrophil depletion, whereas clearance by the spleen was dependent on neutrophils. These experiments further suggest there are neutrophil-dependent and neutrophil-independent mechanisms involved in the removal of C5a and C5a des Arg from the circulation and that binding of C5 fragments in the pulmonary vasculature may precede and then induce neutrophil sequestration.

Animals↗

PubMed1994

Extrarenal tissue distribution of CHIP28 water channels by in situ hybridization and antibody staining.

This study is an extension of in situ hybridization experiments showing expression of mRNA encoding CHIP28 in selected epithelial or endothelia in spleen, colon, lung, and eye (H. Hasegawa, R. Zhang, A. Dohrman, and A. S. Verkman. Am. J. Physiol. 264 (Cell Physiol. 33): C237-C245, 1993). Additional tissues from rat were screened by in situ hybridization, and tissues from rat and humans were stained with a polyclonal anti-CHIP28 antibody. Northern blot showed the 2.8-kilobase mRNA encoding CHIP28 in kidney, lung, and heart. In situ hybridization showed strong hybridization in epithelial cells in choroid plexus, iris, ciliary body, and lens and in epithelial and subepithelial layers of trachea. Except for colonic crypts, specific hybridization was not observed in the gastrointestinal tract, liver, thyroid gland, and muscle. Immunoblot of tissues from exsanguinated rats showed immunoreactive CHIP28 protein in kidney, lung, trachea, and heart. In fixed frozen rat and/or human tissues, the anti-CHIP28 antibody stained epithelial cells in kidney proximal tubule and thin limb of Henle, lung alveolus, bronchial mucosa and glands, choroid plexus, ciliary body, iris, lens surface, colonic crypt, sweat gland, pancreatic acini, gallbladder epithelium, and placental syncytial trophoblast cells. Endothelial cells were stained in many tissues. These studies indicate a wide and selective CHIP28 tissue distribution, suggesting an important role for CHIP28 in fluid transport. The absence of CHIP28 in many nonrenal membranes believed to be water permeable suggests the existence of non-CHIP28 water transporters.

Animals↗

PubMed1995

Pharmacokinetics, oral bioavailability and tissue distribution of azithromycin in cats.

Azithromycin is the first of a class of antibiotics classified as azalides. In an initial experiment four cats were given a single dose of azithromycin 5 mg/kg orally (p.o.), followed 2 weeks later by a single intravenous bolus (i.v.) dose of 5 mg/kg. Subsequently, six cats were given [14C]azithromycin p.o. in a single dose of 5.4 mg/kg for the study of tissue distribution and metabolism. In both experiments, serial blood samples were collected and the plasma assayed for unchanged azithromycin to determine various pharmacokinetic parameters. After p.o. administration, bioavailability was 58% and absorption rapid with a tmax of 0.85 +/- 0.72 h and a Cmax of 0.97 +/- 0.65 microgram/mL. The harmonic mean terminal t1/2 after i.v. administration was 35 h. Tissue half-lives varied from 13 h in fat to 72 h in cardiac muscle. Three metabolites were identified in bile. Unchanged azithromycin accounted for 100% of the total radioactivity in lung and skin tissues when assayed. In comparison with other species, the bioavailability in cats is higher than in humans but lower than in dogs. As in the dog, > 50% of the azithromycin-related material in feline bile was unchanged azithromycin.

Absorption↗

PubMed2005

Tissue distribution of L-fucokinase in rodents.

L-fucose (fucose) is a monosaccharide normally present in mammals and is unique in being the only levorotatory sugar that can be synthesized and utilized by mammals. The metabolism of fucose is incompletely understood, but fucose can be synthesized de novo or salvaged. The utilization of fucose in the salvage pathway begins with phosphorylation by fucokinase. As part of an investigation of fucose metabolism in normal and disease states, we began an investigation of this enzyme. In this report, we present the tissue distribution of the enzyme in rat and mouse. The highest amount of activity was present in brain of both species. Some activity was found in all tissues examined (liver, kidney, heart, lung, spleen, brain, muscle, thymus, white adipose, testes, eye, aorta, small intestine, and submaxillary gland). Very low levels were found in small intestine. Varying levels in the tissues seems most likely to be the result of varying amounts of fucokinase protein as no difference in the Km values of crude enzyme could be shown. Protein-bound fucose levels were determined using the L-cysteine-phenol-sulfuric acid (CPS) assay. There is not a good correlation between fucokinase activity and protein-bound fucose, suggesting some tissues are more active in synthesis of fucose than others.

Animals↗

PubMed1990

Hepatic tissue distribution of doxorubicin-loaded nanoparticles after i.v. administration in reticulosarcoma M 5076 metastasis-bearing mice.

In our previous studies, doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles have been proven to increase dramatically the antitumoral activity of the cytotoxic agent in metastasis-bearing mice. The experimental model consisted of metastases induced by i.v. inoculation of reticulosarcoma M 5076 cell suspension to C57BL/6 mice. The improved efficacy of the drug was noted in terms of either metastasis count or survival. Therefore, tissue-distribution studies of this drug delivery system within the metastatic liver after i.v. administration were undertaken to gain more insight into the mechanism of action. Doxorubicin measurements in healthy hepatic or neoplastic tissue were carried out together with histological examinations using transmission electron microscopy. These results demonstrated the hepatic tissue to be an efficient reservoir of the drug when it was injected associated with nanoparticles. Accumulation of biodegradable nanoparticles with associated doxorubicin in Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug towards the neoplastic tissue.

Animals↗

PubMed1995

Cloning, functional expression and tissue distribution of human alpha 1c-adrenoceptor splice variants.

We report the cloning and characterization of two isoforms of human alpha 1c-adrenoceptor cDNA (alpha 1c-2, alpha 1c-3). These isoforms are generated by alternative splicing and differ from the clone we previously isolated (alpha 1c-1) in their length and sequences of the C-terminal domain. Tissue distribution of mRNAs showed that these variants co-express with alpha 1c-1 in the human heart, liver, cerebellum and cerebrum. Despite the structural differences, functional experiments in transfected CHO cells showed that the three isoforms have similar ligand binding properties, and all couple with phospholipase C/Ca2+ signaling pathway.

Alternative Splicing↗

PubMed1986

Tissue distribution, developmental profile and hormonal regulation of androgen-responsive secretory proteins of rat seminal vesicles studied by immunocytochemistry.

The seminal vesicles of the rat synthesise large amounts of androgen-regulated secretory proteins. Indirect immunofluorescence cytochemistry and immunoblotting with monospecific polyclonal antibodies against three of the major secretory proteins (II, S and F) have been used to investigate the tissue distribution, subcellular localisation, androgen-regulation and developmental profile of secretory protein synthesis. There was no evidence for regional specialisation of the seminal vesicle epithelium; every epithelial cell synthesizes all three proteins via a classical secretory involving storage in secretory vesicles. Proteins S and II are contained within the same secretory vesicles. The time course of deinduction of proteins S and F after castration and their reinduction by testosterone closely followed that for their specific mRNAs described previously. During development, proteins S and F first appear between 10 and 15 days after birth. A protein immunologically related to seminal vesicle protein II is present in the lateral and dorsal lobes of the prostatic complex.

Androgens↗

PubMed1980

Excretion and tissue distribution of radioactive lysinoalanine, N epsilon-DL-(2-amino-2-carboxyethyl)-U-14C-L-lysine (LAL) in Sprague-Dawley rats.

Rats were fed either a control soybean protein diet or a diet containing 3,000 ppm soybean protein-bound lysinoalanine (LAL) for 4 or 6 weeks, at which time all rats were dosed by stomach tube with 14C-LAL labeled in the lysine moiety. Urinary and fecal excretion and tissue distribution were followed in one experiment at 6, 12, 18, 24, 48 and 72 hours. Excretion in urine, feces and expired air was followed in the other metabolic experiment at 2-hour intervals for 48 hours, and at 24-hour intervals for the next 7 days. Tissue samples were counted and LAL determination was made by amino acid analysis in both experiments. The group of rats fed LAL excreted slightly more LAL than the group fed the control diet. Very little LAL remained in the rat tissues after either experiment, and the largest remaining quantity of radioactivity was found as lysine. Quantitation of 14C-lysine in the original material and in the material from rat organs showed that the rat has some capacity for converting LAL to lysine. Less than 0.5% of the original 14C remained in any organ examined 9 days after dosing in the either control or LAL-fed rats. Autoradiographs of the kidneys 24 hours after dosing showed that the radioactive material had accumulated in the proximal convoluted tubules of the corticomedullary junction.

Animals↗

PubMed1985

Tissue distribution and ontogenic appearance of a chicken T lymphocyte differentiation marker.

A monoclonal antibody, designated T10A6, was produced by immunizing mice with H.B14 chicken thymocytes. T10A6, when tested by immunofluorescence, labeled 80% of thymocytes, and a subset of peripheral T cells: 20% of spleen leukocytes, 10% of blood leukocytes, 8% of bone marrow cells but less than 1% of bursal lymphocytes. Tissue distribution on polyethylene glycol sections showed that in the thymus T10A6 stained most cortical thymocytes and a portion of medullary cells. In the spleen, the positive cells appeared scattered mainly in the T-dependent areas. Ontogenic studies revealed that the antigen recognized was found in the chick embryo thymus from day 11 onward and the expression of this antigen on thymocytes reached the adult level from day 13. The first positive cells were detected in the spleen on day 13 of embryonic life. T10A6 (IgG1) precipitated a 65-kDa material from thymocytes. This is the first description of a monoclonal antibody recognizing a peripheral T cell subpopulation in chicken.

Animals↗

PubMed1990

Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. I. Tissue distribution.

Brain-enhanced delivery and sustained release of estradiol (E2) may be potentially useful in the treatments of vasomotor hot flushes and prostatic adenocarcinoma and for fertility regulation. Therefore, we have evaluated a redox-based estradiol-chemical delivery system (E2-CDS) for the brain. The mechanism of this drug delivery is based on an interconvertible dihydropyridine in equilibrium pyridinium salt redox reaction. In this study, we investigated the dose- and time-dependent effects of E2-CDS on the tissue distribution of E2-Q+ and E2, the inactive (intermediate) and active metabolites, respectively, of the E2-CDS. Ovariectomized rats received a single iv injection of E2-CDS at 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg or the drug's vehicle, 2-hydroxypropyl-beta-cyclodextrin (HPCD), on day 0. Tissue samples including brain and peripheral tissues were then analyzed for both E2-Q+ and E2 at 1, 7, 14, 21, or 28 days following the E2-CDS administration. Initially, both E2-Q+ and E2 were detected in all tissues analyzed. The dose-distribution and time-course study demonstrates that (1) at 24 hr (1 day) after administration of E2-CDS, all tissues showed a dose-proportional increase in concentrations of E2-Q+ and E2; (2) the enzymatic oxidation of E2-CDS to E2-Q+ was dose dependent over the 100-fold dose range examined; and (3) the disappearance of E2-Q+ as well as E2 was slow in whole brain and hypothalamus, with an apparent t1/2 = 8-9 days, while both of these metabolites were rapidly cleared from plasma, liver, fat, anterior pituitary, kidney, lung, heart, and uterus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1981

Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats.

The relative toxicity of low doses of lead acetate provided steadily in drinking water or by mouth once per week was studied in weanling and adult rats. Free erythrocyte protoporphyrin and urinary delta-aminolevulinic acid levels were measured, as well as lead levels in blood and kidney. The accumulation of lead in brain tissue and in bone (femur) was measured to determine the effect of age and schedule of administration on tissue distribution and retention of lead. Total intakes of lead during the 60-week experimental period were: weanling and adult rats exposed to drinking water supplemented with 200 microgram of lead acetate/ml: 127 +/- 10 mg and 160 +/- 16 mg, respectively; weanling and adult rats dosed with lead acetate orally once per week: 132 mg and 161 mg, respectively. Increased toxic effects of lead in the weanling animals were apparent in most of the parameters measured (urinary delta-aminolevulinic acid and blood, brain, femur and kidney lead levels). This pattern was observed in weanling rats exposed to lead steadily through drinking water or dosed orally with an equivalent quantity of lead once per week. Lead levels in blood were highly correlated with the accumulation of lead in brain, femur, and kidney tissue in both groups of weanling rats. In adult rats, significant correlations between blood lead and kidney lead and between blood lead and femur lead were found only in the rats receiving lead steadily in drinking water.

Aging↗

PubMed1993

Tissue distribution and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats after intravenous injection.

Male Sprague-Dawley rats (240-290 g) received intravenously a nonlethal (9.25 micrograms/kg) or a lethal (72.7 micrograms/kg) dose of 14C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administered as an emulsion. Animals were euthanized between 5 min and 16 days (lethal dose) or 32 days (nonlethal dose) after treatment. Tissue distribution was considered complete after 24 hr, as by this time radioactivity levels in white adipose tissue had reached a maximum. The highest levels of radioactivity were found in liver (5% of dose/g tissue), followed by white fat (1% of dose/g tissue); serum was lowest at 0.01% of dose/ml serum. Relatively high levels of radioactivity were also detected in most known target organs of TCDD toxicity, e.g., brown fat, adrenals, and thyroid. The pattern of organ distribution of TCDD was essentially the same after the lethal and the nonlethal dose, but did not follow a simple lipophilicity relationship, as levels in liver were higher than those in white fat, and those in brain were extremely low. A pool of TCDD in liposomes initially trapped in lung and spleen was redistributed within 24 hr mainly to liver and adipose tissue. Affinity of TCDD to storage fat seemed to play a more important role as a driving force for redistribution than did induction of cytochrome P450 1A2. The terminal slope of elimination of TCDD from tissues indicated a half-life of 16 days after the nonlethal dose. After the lethal dose radioactivity declined in all tissues for 2 to 8 days and then increased again, reflecting shrinking tissue volumes as well as remobilization of TCDD caused by the process of body mass wasting. Distribution data for 17 tissues and serum were subjected to regression analysis and resulted in up to two uptake phases and up to three elimination phases for a given tissue. After the nonlethal dose TCDD was mainly excreted via feces; combined urinary and fecal excretions occurred with a biological half-life of 16.3 +/- 3.0 days. Much longer half-lives were detected in white fat and skin. After the lethal dose, the fecal excretion of TCDD-derived radioactivity decreased after 8 days, and urinary excretion increased starting 12 days after dosing. Radioactivity in liver and white fat and the extractable portion in feces was mainly unchanged TCDD, as determined by thin-layer chromatography. Radioactivity in urine indicated the presence of a metabolite(s) of TCDD only.

Animals↗

PubMed1994

The tissue distribution of mRNAs for the PACE4 isoforms, kexin-like processing protease: PACE4C and PACE4D mRNAs are major transcripts among PACE4 isoforms.

In the previous study [Biochem. Biophys. Res. Commun. (1994) 200, 943-950] we identified two novel cDNAs (PACE4C and PACE4D) encoding human Kexin-like protease, the PACE4 isoforms. In this study, we examined the expression of PACE4 isoform transcripts in various rat tissues. To detect very low levels and to distinguish among these isoforms, we used the reverse transcriptase-polymerase chain reaction (RT-PCR). PACE4C and PACE4D transcripts were detected in most tissues like PACE4A transcripts, however their tissue distribution profiles and the extent of expression differ. PACE4C and PACE4D transcripts are expressed at a much higher level than PACE4A transcript. These results indicate that PACE4C and PACE4D mRNAs are major transcripts of PACE4.

Animals↗

PubMed1990

Tissue distribution and photosensitizing properties of mono-L-aspartyl chlorin e6 in a mouse tumor model.

Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that possesses properties such as chemical purity and a major absorption band at 664 nm which are potentially exploitable for photodynamic therapy (PDT). The current investigation examined pharmacological and photosensitizing parameters of NPe6 in tumor and normal tissues in mice. [14C]NPe6 was used to obtain quantitative tissue distributions of the photosensitizer as a function of: (a) time following administration; (b) drug dose; (c) mode of drug administration; and (d) tumor size. The in vivo photosensitizing efficiency of NPe6 was compared directly to Photofrin II in experiments which evaluated tumor responses and induction of normal skin damage. Initial PDT experiments demonstrated that NPe6 was ineffective at inducing tumor cures when a 24-h time interval (between drug administration and light treatment) was used. However, PDT-induced tumor cures were obtained when NPe6 was administered 4-6 h prior to light exposure, and these NPe6-PDT treatment parameters were as effective as standard Photofrin II-mediated PDT. Interestingly, the level of PDT-induced normal skin damage was significantly greater for Photofrin II than for NPe6 at comparable drug and light doses. An analysis of pharmacological data and PDT time interval requirements suggests that plasma concentrations of NPe6 may be a more important predictive factor than tumor tissue levels of the photosensitizer for the production of PDT-mediated tumor cures. The results of this investigation indicate that NPe6 is an effective tumor photosensitizer with in vivo clearance properties that eliminate the side effect of prolonged normal skin photosensitization.

Animals↗

PubMed1980

Tissue distribution of 14C-labelled triolein in a soybean oil emulsion. An autoradiographic study in rat and mouse.

A fed and a starved group of mice were injected with a 14C-labelled triolein emulsion, similar to Intralipid, in a dose corresponding to 0.1 mg triglyceride per gram body weight. The animals were sacrificed from 30 sec to 24 h after injection. The tissue distribution of the fat emulsion depended on the nutritional state of the animals. A marked concentration of radioactivity was found in the gastric mucosa of all animals as soon as 30 sec after injection which declined with time but was still clearly discernible in the autoradiograms 24 h after injection. Although the radioactivity only demonstrates the presence of the labelled oleic acid without indication of the degree of triglyceride lipolysis, the autoradiograms showed marked differences in the concentration of radioactivity between the various groups of skeletal muscles and between the different parts of the reticulo-endothelial system.

Animals↗

PubMed1999

Cellular localization and tissue distribution of polycystin-1.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in both kidneys, in addition to a variety of extra-renal manifestations. The PKD1 gene product, polycystin-1, encodes a novel protein with a putative role in cell-cell/cell-matrix interactions. The present study we focused on the (sub)cellular localization of polycystin-1 in cultured cells, and on its tissue distribution in various organs. In Madin Darby canine kidney (MDCK) cells, several polyclonal antibodies showed intense staining at the sites of interaction between adjacent cells, which remained after Triton extraction. Weak cytoplasmic staining was observed. No signal was detected at the free borders of cell aggregates, supporting a role for polycystin-1 in cell-cell interactions. At the tissue level, polycystin-1 expression was observed in specific cell types in tissues with known manifestations of the disease, but also in tissues of organs which have not been reported to be affected in ADPKD. Expression was frequently seen in epithelia, but also in endocrine cells (pancreatic islets, parathyroid-producing cells, clusters in the adenohypophysis, clusters in the adrenal gland, and Leydig cells in the testis). In addition, expression was observed in myocardium and more weakly in myocytes of cardiac valves, of the cerebral arteries, and of skeletal muscles.

Animals↗