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At least 19 recordsLinked to original sources
PubMed1991

Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism.

The nonsteroidal anti-inflammatory agent etodolac (ET) exhibits stereoselectivity in its pharmacokinetics following administration to humans and rats. To underline the factors responsible for this stereoselectivity, the tissue distribution, in vitro tissue binding, and microsomal metabolism of ET enantiomers were studied in the rat. Following iv administration of racemic ET, the S:R AUC ratios in tissues were stereoselective, and different from that in plasma. Binding of enantiomers to tissues was stereoselective, although it did not relate well with in vivo tissue distribution. Rather, the tissue distribution of enantiomers appeared to be better explained by the unbound fractions of enantiomers in plasma. With respect to in vitro glucuronidation by liver microsomes, the Vmax of S-ET was 3.4-fold greater than that of R-ET; the enantiomers possessed similar Km. There appeared to be stereoselectivity in the oxidative metabolism of ET enantiomers by liver and kidney microsomes, in favor of the R-enantiomer. The lower AUC in rat plasma of pharmacologically active S-ET as compared with its antipode is due to its relatively greater distribution to tissues, owing to a lesser degree of binding to plasma proteins, and to its higher rate of glucuronidation.

Animals↗
PubMed2000

Effects of various aluminium compounds given orally to mice on Al tissue distribution and tissue concentrations of essential elements.

To evaluate the risk of gastrointestinal long-term aluminium (Al) exposure, aluminium distribution and the levels of the following essential elements: Ca, Mg, Zn, Cu, and Fe in tissue were studied. Aluminium was administered in drinking water as aluminium chloride, dihydroxyaluminium sodium carbonate or aluminium hydroxide. Mice (strain Pzh:SFIS) were exposed to a total dose of 700 mg Al in long-term treatment (for each Al compound n = 15). Concentrations of Al, Ca, Mg, Zn, Cu, and Fe in stomach, kidneys, bone and liver were analyzed by atomic absorption spectrometry. After AlCl3 treatment, aluminium was found to accumulate in all tested tissues. A significant decrease in Fe concentration in liver and Zn in kidneys was observed in comparison to concentrations of these elements in the control group. In the Al(OH)3-treated group, accumulation of aluminium was observed in bone only and decline of Fe concentration in stomach and Cu in liver and kidney. In the NaAl(OH)2CO3-treated group the increase in Al concentration was significant in bone; there was no change in concentration of essential elements in the examined tissues. The observed aluminium accumulation was not accompanied by changes in Ca and Mg concentration except for bone. This study showed that oral administration as a route of Al exposure can result in diverging accumulation of aluminium in tissues, the concentration depending on the chemical form.

Administration, Oral↗
PubMed1995

Analysis of tissue distribution of valproate in guinea-pigs: evidence for its capacity-limited tissue distribution.

The tissue distribution of valproic acid (VPA) was investigated over a wide range of steady-state plasma levels (Css) in guinea-pigs. The VPA concentrations in various tissues, except the kidney, were all lower than in plasma. Tissue-to-unbound plasma concentration ratios (Kpu) of VPA for adipose, heart, kidney, liver, lung, muscle, pancreas and skin all decreased significantly with increasing unbound plasma concentration (Cuss). The Kpu for brain (0.5-0.9), intestine, spleen and stomach failed to show significant change with Cuss. The disposition of VPA in tissues is adequately described by a model in which VPA was distributed in interstitial and intracellular fluid and bound to interstitial albumin, with limited tissue binding. Tissue binding was extensive only in the kidney. Most of the measured apparent Kpu values agreed well with simulated Kpu values. Steady-state tissue concentration of VPA can be predicted from Css and Cuss when reference data for interstitial albumin and tissue total water are available.

Animals↗
PubMed1982

IgG-Fc and C3 receptors in the chicken: distribution, tissue localization and functional significance.

This paper summarizes data obtained in our laboratory on the demonstration of receptors for IgG-Fc (FcR) and complement (CR) on mononuclear cells of the fowl. A clearcut distinction of these two structures on spleen cells was achieved in rosette assays using SRBC coated with rabbit IgG as indicator cells which bind avian complement, but are not bound by the FcR. The tissue distribution and localization of FcR and CR positive cells was studied in mixed hemadsorption assays on sections of both central (bursa, thymus) and peripheral (spleen) lymphoid organs from normal chickens, as well as lymphocytic infiltrated thyroid glands from animals of the Obese strain (OS) afflicted with spontaneous autoimmune thyroiditis. The possible significance of both receptors in the pathogenesis of this autoimmune process is discussed.

Animals↗
PubMed1997

Tissue distribution of human aldehyde dehydrogenase E3 (ALDH9): comparison of enzyme activity with E3 protein and mRNA distribution.

The tissue distribution of the E3 isozyme of human aldehyde dehydrogenase has been investigated by three methods: enzyme activity assay employing betaine aldehyde as substrate, Western blotting employing E3 isozyme-specific antibodies, and Northern blotting using a human liver E3 cDNA as probe. All three methods showed that E3 isozyme was universally distributed among all tissues tested. The highest levels of the E3 isozyme activity were found in liver, adrenal gland, and kidney. These same tissues also showed highest levels of the E3 protein via the Western blot. This distribution is consistent with the possible physiological role of E3 isozyme in the synthesis of the osmolyte, betaine, and the neurotransmitter, GABA. Northern blot analysis, however, differed from that of enzyme assay and the Western blot in that it showed highest mRNA levels in skeletal and heart muscles, which had low enzyme activities and E3 protein levels.

Adrenal Glands↗
PubMed1992

Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens.

We determined the tissue distribution of 7 human minor histocompatibility (H) Ag. Each of these Ag is defined by one or more MHC class I-restricted CTL clones, previously generated from PBL primed against minor H Ag by HLA-identical bone marrow transplantation (BMT). CTL-mediated lysis of tissue-derived cells and cultured cell lines was used as an in vitro assay for minor H Ag expression of several human tissues. The Ag HA-3 (HLA-A1-restricted), HA-4 (HLA-A2 restricted), HA-6 and HA-7 (HLA-B7 restricted), and the male-specific Ag H-Y (HLA-A2 and B7 restricted) were found to be expressed on cells of all tissues tested. In contrast, the HLA-A2-restricted Ag HA-1 and HA-2 were demonstrated on PHA-blasts, EBV-BLCL, purified T cells, B cells, monocytes, and immature thymocytes, but could not be demonstrated on skin-derived cultured fibroblasts, keratinocytes, melanocytes, cultured epithelial cells of kidney proximal tubili, and umbilical cord vein-derived endothelial cells. Incubation of the latter cell lines with rIFN-gamma, rTNF-alpha, and/or rIL-1 alpha, in concentrations shown to maximally increase their susceptibility to lysis by allo-MHC class I CTL, did not induce recognition by HA-1- and HA-2-specific CTL in vitro. These results indicate an ubiquitous tissue expression of the minor H Ag HA-3, -4, -6, -7 and H-Y in contrast to a to the hemopoietic cell lineage-restricted expression for HA-1 and HA-2. The heterogeneity in tissue expression of T cell-defined, class I-restricted non-MHC Ag implies that they might be derived from intracellular proteins with either an ubiquitous or a more specialized cell type-specific function.

Cytotoxicity, Immunologic↗
PubMed1996

Interactive effects between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl in female B6C3F1 mice: tissue distribution and tissue-specific enzyme induction.

The distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was studied in female B6C3F1 mice. Single doses of TCDD alone (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg), PCB 153 alone (0, 3.58, 35.8, or 358 mg [14C]PCB 153/kg), and all possible combinations of these doses were administered in corn oil, po. At 7 days after dosing, 11 different tissues were analyzed for radioactivity. When TCDD was administered alone, TCDD-derived radioactivity distributed to all tissues in a dose-dependent manner, increasing with dose in the liver, while decreasing (as a percentage of the administered dose) in all other tissues. When PCB 153 was administered alone, the PCB 153 concentration was dose-dependently (percentage of dose) decreased in liver, skin, lung, adrenals, kidney, and blood; no dosimetric effects were observed in the other organs. Coadministration of low doses of both TCDD and PCB 153 resulted in little or no effect on the distribution of either compound. Interactive effects occurred in the pharmacokinetic behavior of both compounds only at higher doses. For example, the amount of TCDD in the liver was increased by 358 mg PCB 153/kg. In most other organs administration of PCB 153 resulted in a dose-dependent decrease in the TCDD content. Coadministration of PCB 153 with 10 micrograms TCDD/kg increased PCB 153 in the liver, but not in other tissues. These results clearly demonstrate that interactive effects on pharmacokinetic behavior occur only at high doses.

Adipose Tissue↗
PubMed2003

Prediction of in vivo tissue distribution from in vitro data. 3. Correlation between in vitro and in vivo tissue distribution of a homologous series of nine 5-n-alkyl-5-ethyl barbituric acids.

PURPOSE: To evaluate the ability to determine accurate in vivo tissue-to-unbound plasma distribution coefficients (Kpue) from in vitro data. METHODS: Fresh pieces of fifteen rat tissues/organs were incubated at 37 degrees C with a homologous series of nine barbiturates covering a wide range of lipophilicity (Log P 0.02 to 4.13). Steady-state in vivo Kpue values were estimated from the tissue and plasma concentrations following simultaneous dosing by constant rate i.v. infusion of all nine barbiturates. Drug concentrations in the tissues and media were determined by HPLC with UV or mass spectrometric detection. RESULTS: The pharmacokinetics of the barbiturate series following constant rate i.v. infusion indicated a range of clearance (0.49 to 30 ml x min(-1) x kg(-1)) and volume of distribution at steady state (0.51 to 1.9 l x kg(-1)) values. Good agreement was observed between the in vitro and in vivo Kpu values, although for the most lipophilic barbiturates the in vitro data underpredicted the in vivo tissue distribution for all tissues. CONCLUSION: The in vitro system for predicting the extent of in vivo tissue distribution works well for compounds of widely differing lipophilicity, although for the most lipophilic drugs it may result in an underprediction of in vivo values.

Animals↗
PubMed1991

Melatonin deacetylation: retinal vertebrate class distribution and Xenopus laevis tissue distribution.

Deacetylation is a rapid clearance mechanism for ocular melatonin. We have studied the distribution of retinal melatonin deacetylase activity among vertebrate classes. Exogenous radiolabeled melatonin is metabolized by ocular tissue prepared from the amphibian Xenopus laevis, the reptile Anolis carolinensis, the teleost fish Carassius auratus, and the bird Gallus domesticus. In contrast, we were unable to detect ocular melatonin breakdown in rat or pig. In each species exhibiting ocular melatonin breakdown, melatonin is first deacetylated to 5-methoxytryptamine, which is deaminated, producing 5-methoxyindoleacetic acid and 5-methoxytryptophol. Deacetylation of melatonin is inhibited by eserine (physostigmine), causing a reduction in the levels of all 3 metabolites. Deamination of 5-methoxytryptamine is inhibited by the monoamine oxidase inhibitor pargyline, such that 5-methoxyindoleacetic acid and 5-methoxytryptophol levels are decreased while levels of 5-methoxytryptamine are increased. Incubation with the deacetylase inhibitor eserine increases endogenous melatonin levels in Xenopus and Carassius eyecups, indicating that endogenous melatonin is metabolized via the deacetylase. We also studied the tissue distribution of the deacetylase in Xenopus laevis. Melatonin deacetylation occurs in retina, retinal pigment epithelium, and skin, all of which are sites of melatonin action. These results indicate that among non-mammalian vertebrates, deacetylation is a common clearance mechanism for ocular melatonin, and may degrade melatonin at other sites of action as well. Melatonin deacetylation may help regulate local melatonin concentration, and generates other biologically active methoxyindoles.

Amidohydrolases↗
PubMed1996

In vivo effects of dexamethasone and sucrose on glucose transport (GLUT-4) protein tissue distribution.

Tissue-specific changes in GLUT-4 were compared in the following three different rat models by inducing varying degrees of hyperinsulinemia with or without hyperglycemia and hypertriglyceridemia: 1) sucrose feeding (Suc), 2) subcutaneous dexamethasone administration (Dex), and 3) a combination of both treatments (Dex/Suc). Suc raised circulatory insulin and triglyceride levels without affecting plasma glucose, whereas both Dex and Dex/Suc induced significant hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. In adipocytes and skeletal muscle, Suc feeding was not associated with any change in total cellular GLUT-4 levels. However, Suc induced a sevenfold increase in fat cell plasma membrane GLUT-4 levels in the basal state and inhibited GLUT-4 translocation in response to insulin. Administration of Dex or Dex/Suc diminished GLUT-4 expression in fat cells, increased it in skeletal muscle, but did not induce any change in heart. Similar to Suc feeding, Dex and Dex/Suc also increased the amount of GLUT-4 detected at the plasma membrane of adipocytes in the basal state and inhibited GLUT-4 translocation in response to insulin. These results emphasize the specific regulation of GLUT-4 in insulin-sensitive tissues.

Adipose Tissue↗
PubMed1998

The murine neutrophil-chemoattractant chemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue distributions, and tissue-specific sensitivities to glucocorticoid regulation in endotoxemia.

Lipopolysaccharide-induced CXC chemokine (LIX) is a novel murine neutrophil-chemoattractant CXC chemokine cloned as a glucocorticoid-attenuated response gene. We investigated LIX message expression in an acute endotoxemia model. LIX message peaks later than KC or macrophage inflammatory protein-2 (MIP-2) and remains elevated longer in almost all tissues. Induced LIX message expression in heart is 5- to 6-fold greater than in lung and spleen, and 20-fold greater than in liver. In contrast, KC expression is equal in heart, lung, and liver, whereas MIP-2 expression is strongest in the lung. Glucocorticoid regulation of these genes also differs. Endotoxemia-induced LIX message expression in the lung is markedly enhanced in adrenalectomized mice and strongly attenuated by dexamethasone, whereas lung KC and MIP-2 expression are unaffected by glucocorticoids. It is surprising to note that endotoxemia-induced brain expression of LIX (but not KC or MIP-2) is increased by dexamethasone. These observations suggest that LIX may have biological roles distinct from KC and MIP-2.

Acute Disease↗
PubMed1996

Tissue distribution, metabolism and excretion of paclitaxel in mice.

So far, all animal pharmacokinetic studies of paclitaxel, which used analytical procedures based on HPLC, have not been sensitive enough to quantify drug levels below 500 ng/ml. Consequently, the interpretation of the results is restricted because drug levels of paclitaxel as low as at least 50 nM (43 ng/ml) are relevant for the pharmacology of this drug. We recently described an accurate and very sensitive method based on HPLC for the determination of paclitaxel and the metabolites 3'-p-hydroxypaclitaxel (I), 6 alpha-hydroxypaclitaxel (II) and 6 alpha,3'-p-dihydroxypaclitaxel (III) in a wide variety of biological matrices. We have now implemented this methodology in a comprehensive pharmacokinetic study in female FVB mice. Previous pharmacokinetic studies in humans demonstrated a large steady-state volume of distribution, indicating that the drug is widely distributed into tissues. Comprehensive tissue distribution studies may, therefore, be helpful in providing more insight into possible relationships between plasma levels, drug levels in tissues and toxicity. Paclitaxel, formulated in Cremophor EL and ethanol (1:1, v/v), was given as a single i.v. bolus dose of 2, 10 and 20 mg/kg to female FVB mice. Except for the brain, the distribution of paclitaxel to all other tissues in the female mice was substantial and maximum drug levels were achieved within 0.5 or 1 h. A marked non-linear increase in the area under the concentration-time curve (AUC) in plasma was observed, which was not paralleled by a proportional increase in the tissue AUC levels. It is postulated that this effect may be related to the substantial amounts of Cremophor EL administered concurrently. The recovery of paclitaxel in the feces (0-96 h) was reduced from 58% at the 2 mg/kg dose level to 44% at the 20 mg/kg dose level. Small amounts of metabolites I and II were detected in the gut, liver and gall bladder, but not in the systemic circulation or any other tissue. Metabolite III was not detected. Metabolites I and II are likely excreted directly into the bile, and since their recovery in the feces accounts for about 25% of the administered dose, their formation thus represents an important pathway of detoxification.

Animals↗
PubMed2001

Tissue distribution of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist, in pigmented rats.

After a single oral administration of 1 mg/kg of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), the radioactivity distribution in tissues of male pigmented rats was studied and compared with that in male albino rats. One eye of each pigmented rat was divided into melanin-containing structures (uvea, pigmented epithelium and sclera) and others without melanin (cornea and lens), and the radioactivity concentration in each ocular tissue was measured. In all the pigmented rat body tissues tested, maximum radioactivity concentrations (Cmax) were reached within 4 h after administration. At 1 h, the kidney showed the highest concentration (11 times the plasma concentration), followed by the urethra, liver, urinary bladder and lung. Concentrations in the other tissues were similar to or less than the plasma concentration. The radioactivity concentrations in most tissues decreased rapidly, being less than 10% of the Cmax 24 h after administration. These characteristics of the 14C-NS-49 tissue distribution in the pigmented and albino rats did not differ. In the eye, however, the radioactivity concentration decreased more slowly in the pigmented than in the albino rats. Most of the radioactivity in the eyes of the pigmented rats was present in melanin-containing structures indicating that NS-49 binds to ocular melanin. The radioactivity concentration in the melanin-containing structures reached a maximum 4 h after administration, then decreased as did that for the whole eye with a t1/2, beta of 66.8 h.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1979

[Studies of intrarenal distribution by macroautoradiogram and tissue distribution of 99mTc-gluconate (author's transl)].

1) The experimental studies have demonstrated that 99mTc-gluconate reaches a high concentration in the kidneys within 1-2 hours after injection and its concentration in organs adjacent to the kidney is low. 2) The initial images of serial macroautoradiograms visualized the inner medulla as well as the cortex and outex medulla, whereas the delayed images revealed only the outer cortex and outer stripes in the outer medulla. These findings suggest that this renal agent consists of two components and the delayed component deposits in the convoluted and straight segments of proximal tuble. 3) This renal agent visualizes the calyceal system and excretory pathways in the initial study and the renal morphology in the delayed study. Therefore, using this renal agent, it may be possible to evaluate a variety of renal diseases, including obstructive uropathy, space-occupying lesions, congenital deformities, etc,.

Animals↗
PubMed1984

Effect of sulfaphenazole on tolbutamide distribution in rabbits: analysis of interspecies differences in tissue distribution of tolbutamide.

The effect of sulfaphenazole on the distribution of tolbutamide was examined by comparing the change in the steady-state volume of distribution (Vdss) determined from in vivo plasma elimination with the tissue-to-plasma concentration ratio of various tissues (Kp) in rabbits; this effect was compared with that previously reported in rats. In rabbits, the Kp values of six tissues studied (i.e., brain, heart, spleen, small intestine, muscle, and skin) increased in the presence of sulfaphenazole ; except for brain, lung, and adipose tissue, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did show a significant decrease. This suggested that both the tissue and plasma protein binding of tolbutamide were affected by sulfaphenazole and that the increase in Kp was due mainly to the displacement of plasma protein binding of tolbutamide by sulfaphenazole , which was greater than that of tissue binding, while no change in Kp was due to a parallel change in both the plasma protein binding and tissue binding of tolbutamide. In both rabbits and rats, the Vdss calculated from plasma concentration versus time curve was very close to that calculated from the Kp values and volumes of various tissues in the presence and absence of sulfaphenazole , respectively. The interspecies difference of the effect of sulfaphenazole on the tissue distribution of tolbutamide between rabbits and rats was elucidated from both in vivo tissue distribution and in vitro plasma protein binding studies.

Animals↗