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PubMed2006

Ghrelin tissue distribution: comparison between gene and protein expression.

Ghrelin, the natural ligand of the GH secretagogue (GHS) receptor, was originally isolated from the stomach and detected in several tissues, but a systematic study of its tissue distribution has not been performed. In the present investigation, we evaluated ghrelin gene expression (by RT-PCR technique) and ghrelin protein concentration (by enzyme immunoassay technique) in tissues obtained from control rats as well as in rats subjected to 48-h fasting. The ghrelin gene was expressed in stomach, small intestine, brain, cerebellum, pituitary, heart, pancreas, salivary gland, adrenal, ovary and testis, with maximum expression occurring in the stomach, while no significant expression was detected by standard RT-PCR in liver, lung, kidney and skeletal muscle. Ghrelin protein was detected in stomach, small intestine, brain, cerebellum, pituitary, lung, skeletal muscle pancreas, salivary gland, adrenal, ovary and testis, at concentrations ranging from 0.05 to 1.43 ng/mg of homogenate protein (the highest concentration occurred in the lung, followed by the brain). Ghrelin was not detectable in the heart, liver and kidney. Therefore, gene and protein expression were dissociated. Fasting did not produce significant changes in ghrelin gene expression, while the distribution of ghrelin between different tissues was significantly modified: protein concentration increased in the brain, cerebellum, lung and salivary gland, while it decreased in the stomach.

Animals↗

PubMed1999

Influence of human anti-lipopolysaccharide immunoglobulins on tissue distribution and clearance of lipopolysaccharide in rats.

To examine the influence of passive immunization on the biological fate of injected lipopolysaccharide (LPS), we used a human IgG preparation (anti-LPS IgG) rich in antibodies to a large panel of smooth and rough purified LPS extracts as well as a normal IgG preparation (standard IgG). Our approach was to compare the uptake of 125I-labeled LPS by the tissues of saline or IgG-treated rats. After intravenous injection, one fraction of 125I-labeled Escherichia coli O55:B5 LPS is rapidly taken up by tissues, while another fraction remained in the blood. Uptake of 125I-labeled LPS was principally observed into the liver and spleen. In rats treated prophylactically with standard IgG, these tissues accumulated significantly larger amount of LPS than the tissues of rats treated with anti-LPS IgG. Nevertheless, both IgG preparations increased the specific binding of LPS by the liver and spleen. High levels of homologous unlabeled LPS decreased the uptake of LPS by the liver, presumably by occupying tissue receptors, whereas in the presence of E. coli O127:B8 LPS, an increase of the uptake of 125I-labeled LPS by the liver and lungs was observed. The pharmacokinetics and tissue distribution of LPS-IgG complexes pre-formed in vitro were compared. In the presence of standard IgG, a unexpected increase of the uptake of LPS by the tissues was recorded, whereas LPS-anti-LPS IgG complexes decreased the binding of 125I-labeled LPS to the tissues. On the other hand, the vascular effects induced by LPS did not appear to be modified in rats pretreated with either IgG preparation. In conclusion, although passive immunization against LPS slightly modified the uptake and clearance of LPS, neither in vitro nor in vivo formation of LPS-anti-LPS IgG complexes afforded a very significant protection against the toxic effects of LPS.

Animals↗

PubMed2004

Tissue distribution of molidone in a multidrug overdose.

Molindone hydrochloride (Moban) is a dihydroindolone compound dissimilar in structure to other antipsychotic drugs (i.e., phenothiazines, butyrophenones, dibenzepines, and thioxanthenes). The antipsychotic (or neuroleptic) activity of molindone makes it particularly useful in the treatment of schizophrenia. There are a few published cases which report the tissue distribution of molindone in the human body. We report the analysis of molindone in postmortem samples using a solvent mixture (toluene/hexane/isoamyl alcohol) base extract followed by an acid (0.5M H(2)SO(4)) wash. Molindone was identified by gas chromatography-mass spectrometry (m/z 100, 176, 276) and quantitated using a gas chromatograph and nitrogen-phosphorus detector. The range of linearity was 0.1 mg/L to 5.0 mg/L. We report our findings of molindone concentrations in blood, liver, bile, gastric, and urine as follows: 6 mg/L in blood; 26 mg/kg in liver; 23.1 mg/L in bile; 1200 mg/L in gastric; and 37.3 mg/L in urine. Vitreous lithium (5.9 mmol/L) was determined by flame atomic absorption spectrometry. The medical examiner listed the cause of death as a combined drug overdose of molindone and lithium. The tissue results are compared with another case and the pharmacology of molindone is presented.

Adult↗

PubMed1981

Technetium radiopharmaceuticals: chemical characterization and tissue distribution of Tc-glucoheptonate using Tc-99m and carrier Tc-99.

The chemical structure of the kidney- and brain-imaging agent Tc-99m glucoheptonate has been established using the Tc-99 isotope. In a comparative study between Tc-99 and Tc-99m glucoheptonates, chromatographic, electrophoretic, and tissue distribution studies showed identical compounds in 0.9% NaCl. Optimal conditions for the formation of the Tc-99 glucoheptonate complex were investigated by uv and visible spectroscopy. The oxidation state of Tc-99 in the compound is V, measured by Sn2+ titration. The complex contains a Tc = O core and two glucoheptonate ligands (oxobis(glucoheptonato)technetate(V) anion (net charge: -1) in aqueous solution). NMR studies demonstrated two five-membered glucoheptonate rings, bidentate bound to Tc by the oxygens of the end carboxyl group and the adjacent hydroxyl group. The compound is stabilized by interaction between Tc-99 and one of the hydroxyloxygens of glucoheptonate at the vacant coordination site trans to the Tc = O core. Experiments with the reducing agent NaBH4 demonstrated the absence of Sn (II or IV) in the complex and a biological behavior independent of the reducing agent used.

Animals↗

PubMedDate not supplied

The effect of certain variables on the tumor and tissue distribution of tracers. Part 1; Carrier.

Buffalo rats bearing thigh-implanted strain-7777 Morris hepatomas were used as a model for studying the effect of carrier material on the body distribution, tumor uptake, excretion, and tumor-to-background ratios of 67Ga and 54Mn. An effort was also made to observe the changes in 67Ga and 54Mn concentrations induced by carrier in viable tumor and skeletal muscle, relative to their interstitial fluid space. This value is referred to as the Tissue Distribution Index. Carrier manipulation resulted in striking changes in the distribution of the two ions from the carrier-free state. The data also indicated a difference in the pharmacodynamics of 67Ga and 54Mn in malignant and healthy tissues which could be of importance to nuclear medicine and oncology.

Animals↗

PubMed1985

Tumor uptake of radiolabelled pyrimidine bases and pyrimidine nucleosides in animal models--VIII. Synthesis and tissue distribution of N-[2-(hydroxyethoxy) methyl]-5-[3H]methyluracil.

The tritium-labelled acyclonucleoside, N-[2-(hydroxyethoxy)methyl]-5-[3H]methyluracil (3H-3), was synthesized for evaluation as a tumor diagnostic agent. 5-[3H]-Methyluracil, 3H-1, was converted to the 2,4-bis-trimethylsilyl intermediate which was coupled with 2-acetoxyethoxymethyl bromide to afford 1-[(2-acetoxyethoxy)methyl-5-[3H]methyluracil (3H-2). Treatment of 3H-2 with sodium methoxide in methanol afforded 3H-3 (specific activity 188 MBq mmol-1. The tissue distribution of 3H-3 was examined in male BDF1 mice bearing Lewis Lung (LL) carcinomas. Long bone exhibited the highest tumor: tissue ratios. The kidney contained the highest radioactivity level relative to the tumor. This suggested a major urinary route of excretion. The major radioactive blood component (89.21%) was found to have a biological half-life of 0.19 min. The title compound is unsuitable for use as a diagnostic agent for LL carcinoma because of low tumor uptake and rapid urinary elimination of injected radioactivity from the body.

Animals↗

PubMed1976

Tissue distribution of 14C-labeled ethylene disbromide in the guinea pig.

A study was undertaken to determine the tissue distribution of uniformly 14C-labeled ethylene dibromide in guinea pigs following intraperitoneal administration. Organs containing the greatest concentration of radioactivity per unit weight (kidneys, liver, adrenals, pancreas, and spleen) were the same organs in which pathologic changes have been reported by other investigators, indicating a direct correlation between tissue levels and target organ toxicity. The principal route of excretion was via the kidneys, 66% of the dose appearing in the urine within 72 hours of administration. Fecal excretion for the 72 hour period was relatively insignificant, representing less than 3% of the dose.

Animals↗

PubMed1989

Tissue distribution of 125I-labelled carbonic anhydrase isozymes I, II and III in the rat.

Carbonic anhydrase (CA) isozymes CA I and CA II were isolated from rat erythrocytes, and CA III from rat skeletal muscle. They were purified to homogeneity and labelled with 125I using the Bolton-Hunter method. The tissue distribution of these [125I]CA isozymes was studied in rats with whole-body autoradiography at various times after an intravenous injection. The distribution pattern showed a remarkable organ specificity. CA I and CA III were to a great extent localized to the renal cortex. This is compatible with renal uptake, secondary to glomerular filtration, of these isozymes. This would be expected from the renal handling of proteins with the following characteristics: molecular weight of 29,000; iso-electric points, pI, around 7.2 and 6.5 respectively. However, CA II of similar molecular shape and size, with a pI of 6.8, remained in the blood and was preferentially localized to the liver. Further studies are needed to clarify why such similar proteins are targeted to different organs.

Animals↗

PubMed1986

Tissue distribution, metabolism, anticonvulsant efficacy and effect on brain amino acid levels of the glia-selective gamma-aminobutyric acid transport inhibitor 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol in mice and chicks.

Using tritium-labelled 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) its tissue distribution and metabolism were investigated in adult mice and 4-day-old chicks after systemic administration of the drug. It was found not to be significantly metabolized in the brain since metabolites of THPO corresponding to only approximately 8% of the parent compound could be detected 30 min after administration of the drug intramuscularly in mice. In the liver, however, THPO was found to be metabolized to a considerable extent. In chicks THPO metabolites were found in the brain but they accounted for less than 35% of the radioactivity. The brain concentration of THPO in mice and chicks corresponded to respectively 10 and 50% of the dose injected intramuscularly and the tissue level was essentially constant for at least 3 h after injection. Following systemic administration of THPO to mice and chicks the contents of aspartate, glutamate, glutamine, and gamma-aminobutyric acid (GABA) in whole brain and in synaptosomes was determined. It was found that only GABA contents were affected being increased in synaptosomes from mice and decreased in whole brain in chicks. Doses of THPO, which in chicks but not in mice led to brain levels that were sufficient to inhibit glial GABA uptake, were found to protect chicks but not mice against isonicotinic acid hydrazide-induced seizures. The findings are compatible with the notion that THPO exerts its anticonvulsant activity by inhibition of astrocytic GABA uptake.

Amino Acids↗

PubMedDate not supplied

The widespread occurrence and tissue distribution of the imidazolopyrazine luciferins.

Bioluminescence has been reported to occur in 17 phyla and at least 700 genera. However, the luciferin chemistry of the majority of luminous organisms has yet to be determined. The most common chemistry which is known to occur in deep sea bioluminescence is imidazolopyrazine bioluminescence. The main aim of this study was to examine the phyletic and tissue distribution of imidazolopyrazine luciferins. This will facilitate analysis of imidazolopyrazine bioluminescence at the cellular and molecular levels and, in particular, how and when its chemistry is controlled and expressed in vivo. Assays for both known imidazolopyrazines were established and a range of fresh organisms and tissue were analysed, i.e. fish, cephalopods, copepods, ostracods, amphipods and euphausiids. The main findings were that the number of genera in which coelenterazine has been detected has been increased from 52 to about 90. Also, for the first time, the other known imidazolopyrazine luciferin, Vargula-type luciferin, was quantified in the ostracod Cypridina dentata, but was not detected in any of its potential predators. Neither imidazolopyrazine luciferin was found in several luminous stomiiform fish assayed. Coelenterazine was measured in the livers and photophores of a number of cephalopods and it is apparent that coelenterazine is responsible for both modes of luminescence.

Animals↗

PubMed1990

Tissue distribution of a brain-enhanced chemical delivery system for estradiol.

Enhanced delivery and sustained release of estradiol (E2) in the brain could have potential clinical applications in the effective treatment of vasomotor "hot flushes" and prostatic cancer. We have, therefore, evaluated a brain-enhanced E2-chemical delivery system (E2-CDS), which is based upon the interconvertible dihydropyridine in equilibrium with pyridinium salt redox reaction. In this study, we evaluated the tissue distributions of E2-Q+ and E2--the inactive and active metabolites of the E2-CDS. Both E2-Q+ and E2 were detected in all tissues analyzed. In peripheral tissues, E2-Q+ and E2 were rapidly cleared, but in brain, concentrations of both compounds exhibited a slow decline with a t1/2 = 8 days. 14 Days after the E2-CDS administration, brain levels of E2-Q+ exceeded plasma levels by 170-fold, fat levels by 20-fold, and liver levels by 8-fold. Similarly, brain-E2 levels exceeded plasma levels by 38-fold, fat levels by 11-fold, and liver levels by 7-fold. Furthermore, levels of E2-Q+ In anterior pituitary, kidney, heart, and lung were initially 2- to 6-fold higher than brain levels, but 14 days after the E2-CDS administration, brain levels of E2-Q+ exceeded E2-Q+ levels in these peripheral tissues by 1.5- to 3-fold. The increased brain/peripheral tissues ratios of E2-Q+ and E2 in rats treated with the E2-CDS support brain-enhanced delivery and sustained release of E2 from this delivery system.

Animals↗

PubMed2006

Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs.

Astragaloside IV, a natural product purified from the Chinese medical herb Astragalus membranaceus (Fisch) Bge, is now being developed as a cardioprotective agent for treating cardiovascular diseases. The purpose of the present study was to examine in vivo pharmacokinetics and tissue distribution in both rats and dogs by using an established high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry quantitative detection method. Astragaloside IV showed moderate to fast elimination; the elimination half-life of astragaloside IV was 98.1, 67.2 and 71.8 min in male rats, and 34.0, 66.9 and 131.6 min in female rats at doses of 0.75, 1.5 and 3.0 mg/kg, respectively. There was no significant difference in systemic clearance at three dose levels, suggesting that astragaloside IV may have linear pharmacokinetic characteristics in rats within the dose ranges tested. The highest concentration of astragaloside IV was detected in the lung and liver. However, limited distribution to the brain, indicates that astragaloside IV may have difficulty penetrating the blood brain barrier. In addition, only about 50% of the parent astragaloside IV was recovered in both urine and feces. These results indicate that there was about 83% astragaloside IV binding to plasma protein and that the binding to the plasma is linear at the concentration range of 250-1000 ng/ml. As in rats, astragaloside IV may have linear pharmacokinetic characteristics in dogs within the dose ranges tested. Astragaloside IV was slowly cleared via hepatic clearance with a systemic clearance (CL) of about 0.004 l/kg/min. Based on the favorable pharmacokinetic properties in both rats and dogs, astragaloside IV warrants further investigation for the prevention of cardiovascular diseases.

Animals↗

PubMed1998

Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter.

We report the cloning, sequence analysis, tissue distribution, functional expression, and chromosomal localization of the human pancreatic sodium bicarbonate cotransport protein (pancreatic NBC (pNBC)). The transporter was identified by searching the human expressed sequence tag data base. An I.M.A.G.E. clone W39298 was identified, and a polymerase chain reaction probe was generated to screen a human pancreas cDNA library. pNBC encodes a 1079-residue polypeptide that differs at the N terminus from the recently cloned human sodium bicarbonate cotransporter isolated from kidney (kNBC) (Burnham, C. E., Amlal, H., Wang, Z., Shull, G. E., and Soleimani, M. (1997) J. Biol. Chem. 272, 19111-19114). Northern blot analysis using a probe specific for the N terminus of pNBC revealed an approximately 7.7-kilobase transcript expressed predominantly in pancreas, with less expression in kidney, brain, liver, prostate, colon, stomach, thyroid, and spinal chord. In contrast, a probe to the unique 5' region of kNBC detected an approximately 7.6-kilobase transcript only in the kidney. In situ hybridization studies in pancreas revealed expression in the acini and ductal cells. The gene was mapped to chromosome 4q21 using fluorescent in situ hybridization. Expression of pNBC in Xenopus laevis oocytes induced sodium bicarbonate cotransport. These data demonstrate that pNBC encodes the sodium bicarbonate cotransporter in the mammalian pancreas. pNBC is also expressed at a lower level in several other organs, whereas kNBC is expressed uniquely in kidney.

Amino Acid Sequence↗

PubMed1992

Nearly ubiquitous tissue distribution of the scrapie agent precursor protein.

The "modified host protein" model of scrapie proposes that the transmissible agent is composed of the degradation-resistant protein, Sp33-37, and that clinical and pathologic signs result from neurotoxic accumulations of this protein. Sp33-37 is an abnormal, amyloidogenic isoform of the normally occurring cellular protein Cp33-37. This study investigated the tissue distribution of Cp33-37 in hamster. In brain, Cp33-37 was most concentrated in the hippocampal formation. Immunohistochemical studies localized Cp33-37 to neurons and surrounding neuropil in hippocampus; septal, caudate, and thalamic nuclei; dorsal root ganglia cells; and large-diameter dorsal root axons. In non-neuronal hamster tissues, Cp33-37 was detected in circulating leukocytes, heart, skeletal muscle, lung, intestinal tract, spleen, testis, ovary, and some other organs. The presence of Cp33-37 in extracerebral tissues indicates that its function is not unique to brain. These results indicate that the molecular substrate for the production of Sp33-37, the scrapie agent, and scrapie amyloid is present in a variety of cerebral and extracerebral sites.

Animals↗

PubMed2002

Ontogeny, tissue distribution, and hormonal regulation of insulin-like growth factor binding protein-2 (IGFBP-2) in a marine fish, Sparus aurata.

In this study, we have cloned insulin-like growth factor binding protein (IGFBP)-2 from a marine hermaphroditic fish species, the gilthead sea bream (Sparus aurata), and determined its structure, ontogeny, tissue distribution, and hormonal regulation. The sea bream IGFBP-2 precursor consists of 286 amino acids, including a putative signal peptide of 22 residues and a mature protein of 264 residues. The overall sequence of sea bream preIGFBP-2 is 52-39% identical to that of zebrafish, chick, mouse, rat, pig, sheep, bovine, and human preIGFBP-2. The cysteine-rich N- and C-terminal domains, which are believed to be important for IGF binding, show a greater degree of conservation with a sequence identity of 73-56% and 53-50%, respectively. Sea bream IGFBP-2 contains 18 cysteine residues and their alignment is identical to those of other vertebrate IGFBP-2s. The Arg-Gly-Asp (RGD) sequence, present in the C-terminal domain of all known IGFBP-2, is also present in the sea bream. Northern blot analysis of RNA samples extracted from adult liver and developing larvae, revealed two transcripts of about 1.3 and 2.5 kb. RT-PCR analysis showed that IGFBP-2 was expressed in all adult tissues studied, with the highest levels found in liver and skin. IGFBP-2 transcripts were detected in gonad during reproductive cycle of S. aurata. Highest levels of IGFBP-2 mRNA were found in bisexual young gonads, and the levels decreased with gonad development and relatively high levels of IGFBP-2 mRNA were found in the ovary during spawning. By contrast, testicular IGFBP-2 mRNA levels were very low. RT-PCR detected IGFBP-2 mRNA throughout development in unfertilized eggs, embryos, and larvae, with highest levels observed after day 3 post-hatching, suggesting that this mRNA is the product of both the maternal and embryonic genomes. High variability in steady-state levels of hepatic IGFBP-2 mRNA was noted in adult fish, resulting in a statistically insignificant response to growth hormone treatment. These results suggest that the structure of IGFBP-2 is conserved in sea bream and that IGFBP-2 mRNA is expressed during early development and in gonad during the reproductive cycle, suggesting that it may play a role in gilthead sea bream development and reproduction.

Amino Acid Sequence↗

PubMed1991

Intestinal absorption and tissue distribution of [14C]pyrroloquinoline quinone in mice.

Pyrroloquinoline quinone (PQQ) functions as a cofactor for prokaryotic oxidoreductases, such as methanol dehydrogenase and membrane-bound glucose dehydrogenase. In animals fed chemically defined diets, PQQ improves reproductive outcome and neonatal growth. Consequently, the present study was undertaken to determine the extent to which PQQ is absorbed by the intestine, its tissue distribution, and route of excretion. About 28 micrograms of PQQ (0.42 microCi/mumol), labeled with 14C derived from L-tyrosine, was administered orally to Swiss-Webster mice (18-20 g) to estimate absorption. PQQ was readily absorbed (62%, range 19-89%) in the lower intestine, and was excreted by the kidneys (81% of the absorbed dose) within 24 hr. The only tissues that retained significant amounts of [14C]PQQ at 24 hr were skin and kidney. For kidney, it was assumed that retention of [14C]PQQ represented primarily PQQ destined for excretion. For skin, the concentration of [14C]PQQ increased from 0.3% of the absorbed dose at 6 hr to 1.3% at 24 hr. Furthermore, most of the [14C]PQQ in blood (greater than 95%) was associated with the blood cell fraction, rather than plasma.

Administration, Oral↗

PubMed2000

[Pharmacokinetics and tissue distribution of azithromycin in humans].

Azithromycin(AZM) is a new macrolides antibiotic developed by Pfizer Inc. of the US. It has a 15-membered ring structure obtainable by introducing methyl-substituted nitrogen into a 14-membered ring lactone of erythromycin(EM). An effective drug concentration is sustained long owning to its superiority in tissue distribution and long half life(T1/2). AZM is also demonstrated to be twice to three times more powerful than the existing macrolides owning to its reinforced antimicrobial activity against Gram-negative microorganisms including influenza virus. AZM is already used in clinical practice in foreign countries and its excellent clinical performance has been demonstrated by the data. As for the domestic basic and clinical studies of AZM, Phase I study was initiated in 1991 following completion of nonclinical studies, and general clinical studies, a dose-setting study and Phase III controlled studies were conducted between 1992 and 1994. Usefulness of AZM is substantiated by the data from those studies.

Anti-Bacterial Agents↗

PubMed1991

Tissue distribution of bovid herpesvirus-4 in inoculated rabbits and its detection by DNA hybridization and polymerase chain reaction.

A DNA hybridization technique, using the polyrepetitive EcoRI L-fragment of bovid herpesvirus (BHV-4) as a probe, was developed to determine virus distribution in the tissues of BHV-4-infected pregnant rabbits. The cloned fragment did not react with the DNA of rabbits or of other herpesviruses, e.g., infectious bovine rhinotracheitis, bovine herpes virus mammillitis, and pseudorabies viruses. The detection limit was 10(-13) g of DNA or approximately 600 genome equivalents of viral DNA, which indicates a level of sensitivity of one viral genome per 500 cells in our assay. Using conventional cell culture techniques, the virus was isolated from only one of fifteen infected rabbits and a few aborted fetuses. However, when organ culture or dot blot hybridization was used, BHV-4 was detected in all rabbits and their fetuses. Viral DNA was detected by DNA hybridization in spleen, ovary, uterus, lung, liver, salivary gland, lymph node, and placentome of adult rabbits and in a composite of fetal tissues. When polymerase chain reaction (PCR) was used, the virus was detected in several organs (including the nervous tissues) that were found negative by other techniques. These results indicate that blot hybridization and PCR are more sensitive than conventional techniques for studying the pathogenesis of BHV-4 in animals. The data obtained by these methods suggest that BHV-4 may be maintained in infected rabbits in a latent state in a variety of tissues including the nervous system.

Animals↗