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PubMedDate not supplied

Human Ia-like antigens (Analysis of the tissue distribution and immunochemical profile with monoclonal antibodies).

Analysis of the tissue distribution of human Ia-like antigens has shown that they have a wider distribution than originally reported. Furthermore, the expression of Ia-like antigens may change when cells undergo malignant transformation: for instance, melanoma cells acquire Ia-like antigens, while breast carcinoma cells lose them. Serological and immunochemical analysis of Ia-like antigens with monoclonal antibodies has shown a cellular and molecular heterogeneity of these molecules which had not been previously recognized with conventional allo- and xenoantisera. The functional significance of this heterogeneity is not known. Monoclonal antibodies to human Ia-like antigens cross-react with lymphocytes from other animal species indicating that portions of the molecules have been conserved during evolution. The biological implications of these findings are discussed.

Animals↗

PubMed2001

Compartmental pharmacokinetics and tissue distribution of the antifungal echinocandin lipopeptide micafungin (FK463) in rabbits.

The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 microg/ml at 0.5 mg/kg to 16.8 microg/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 microg x h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 microg/g), liver (2.05 to 8.82 microg/g), spleen (1.87 to 9.05 microg/g), and kidney (1.40 to 6.12 microg/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 microg/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.

Animals↗

PubMed1989

Organic nitrate reductase: reassessment of its subcellular localization and tissue distribution and its relationship to the glutathione transferases.

1. Using a specific and sensitive GLC method for the determination of glyceryl trinitrate (GTN), its subcellular and tissue distribution were reassessed. Liver was the most active tissue, but activity was also detected in the heart, kidney and gut. In all tissues activity was localized in the soluble fraction. The activity of soluble glutathione S-transferase followed the same pattern, liver exhibiting the highest and the heart the lowest activity. 2. Pretreatment with phenobarbitone and 3-methylcholanthrene stimulated both the glutathione S-transferase and organic nitrate reductase activities. 3. Glutathione S-transferase activity was competitively inhibited by GTN. 4. A comparison of the plasma and hepatic metabolism of GTN revealed higher drug affinity for the hepatic enzyme.

Animals↗

PubMed1978

Blood and tissue distribution of gamma glutamyl transferase in calves.

In five male and five female calves, we studied the tissue distribution of gamma-glutamyl transferase. The enzyme was mainly in kidney, pancreas, and liver; there was no sex-related difference. The relative hepatic and pancreatic specificity of the enzyme indicated that the measure of its activity in serum could be a test of hepatic or pancreatic damage in the calf. Serum activity measured within 159 samples of apparently healthy calves was 15.3 +/- 3.7 U/liter, not differing significantly from that of adult cow.

Animals↗

PubMed1993

Blood clearance and tissue distribution of various formulations of alpha-tocopherol injection after intravenous administration.

The in vivo elimination and tissue distribution (2 h after administration) of various types of formulations of alpha-tocopherol as a model drug were examined in rats. An organic cosolvents formulation of alpha-tocopherol (alpha-tocopherol/EtOH/polyethylene glycol 400) was rapidly removed from the blood circulation, the ratio of the distributed alpha-tocopherol was 20% in the lungs, about 70% in the liver and about 10% in the spleen. The main reason for this was considered to be the appearance of droplets more than 10 microns in diameter in the blood. Elimination of the micelle formulation using Brij58 from the blood was the most rapid, followed by Tween80 and HCO60. This order is thought to be due to the difference in the polyoxyethylene group among these surfactants. In liposome formulations, liposomes having a diameter of about 80 nm were the most stable in the blood circulation, and alpha-tocopherol was distributed in the reticuloendothelial system (RES) in the smallest ratio. The uptake of liposomes by the spleen and lungs depended on the liposome size. The uptake by the liver was in the decreasing order of 28 nm >> 42 nm, 151 nm, 195 nm, 3656 nm > 106 nm > 75 nm. The 100 nm lipid emulsion was eliminated from the blood more rapidly than the 100 nm liposome formulation.

Animals↗

PubMedDate not supplied

Tumor and tissue distribution of 125I-labeled natural and antitumor antibodies in murine experimental tumor systems.

The binding and tissue distribution of 125I-labeled rabbit anti-sarcoma 180 (S-180) immunoglobulin G (IgG) (RAS-180G), normal rabbit IgG (NRG) and ICR mouse IgGs from normal (NMG) and S-180-bearing ICR mice (AS-180G) were studied in ICR mice bearing S-180. 125I-labelled IgGs preparted from normal (NC57G) or Adenocarconoma 755 (Ca 755)-bearing C57BL/6 mice (A755G) were also examined in C57BL/6 mice bearing ca755. Not only RAS-180G and AS-180G but also NRG and NMG persisted in the tumor site. This result suggests that allogeneic natural IgG could be used as a carrier protein for antitumor agents.

Adenocarcinoma↗

PubMed1986

Tissue distribution of subcutaneously administered aluminum chloride in weanling rabbits.

The purpose of our investigation was to determine blood and tissue levels of aluminum (Al) in normal young rabbits. Furthermore, we wished to determine tissue distribution and accumulation of Al as related to its blood concentration in Al-dosed rabbits. The levels of Al accumulated were determined in different tissues of growing rabbits after continuous subcutaneous administration of Al chloride (3.78 mg/d) for 28 d. No signs of toxicity were apparent from comparisons of hematocrit or weight gain between control and Al-dosed rabbits. The largest concentration of the Al was observed in bone, which was also found to have the highest levels in the control rabbit tissues. Following bone, the experimental animals showed the greatest increase of Al levels in kidney cortex, kidney medulla, liver, testes, skeletal muscle, heart, brain white matter, and brain hippocampus, in that order. No significant difference was found in brain grey matter between control and experimental animals. As the brain tissue of the Al-treated animals had the lowest Al level of the tissues measured, it appears that there is a partial blood-brain barrier to entry of Al.

Aluminum↗

PubMed1986

Factors influencing the tissue distribution of coenzyme Q10 intravenously administered in an emulsion to rats: emulsifying agents and lipoprotein lipase activity.

The tissue distribution of coenzyme Q10 (CoQ10) administered intravenously in an emulsion prepared with egg yolk phosphatidylcholine (PC), egg yolk sphingomyelin (SPM) or a combination of PC and a polyoxyethylene derivative of hydrogenated castor oil (HCO-60) (PC + HCO-60) was investigated. The disappearance from the plasma of CoQ10 administered in three different emulsions of lipid particle size less than 0.5 micron varied with the particular emulsifier. Its disappearance occurred most rapidly from the PC emulsion; with the addition of HCO-60, its disappearance was much slower. In the reticuloendothelial system, the concentration of CoQ10 was higher in the spleen, for both the SPM and PC + HCO-60 emulsions than for the PC emulsion. HCO-60 reduced the CoQ10 distribution in the liver from the PC emulsion. Differences in disappearance rates from the plasma are thus considered to be due to the extent of CoQ10 distribution in the liver. CoQ10 concentration in the heart, a target organ, was greatest with the PC emulsion. Its distribution was related to lipoprotein lipase (LPL) activity in this organ. The effects caused by HCO-60, however, could not be explained by LPL activity alone. CoQ10 distribution in the adrenal gland and kidney can be explained partly by LPL activity but in the presence of HCO-60, the distribution mechanism apparently involves other factors.

Animals↗

PubMedDate not supplied

Effect of whole-body hyperthermia on pharmacokinetics and tissue distribution of doxorubicin.

The effect of whole-body hyperthermia (41.5 degrees C, 2 h) on doxorubicin (DOX) tissue distribution and plasma pharmacokinetics was examined in rats bearing a subcutaneous fibrosarcoma. Tumour response to the hyperthermia regimen alone was minimal, but the combination of heat with DOX (5.0 mg/kg, i.v.) enhanced tumour growth delay. The combined therapy, however, showed increased toxicity to normal tissue (especially renal and cardiac). Although DOX levels in spleen tissue were higher in rats exposed to hyperthermia than in control normothermic rats, both groups had comparable levels of drug in tumour, heart, kidney, and small intestine tissue at all time-points examined. Compared with normothermic animals, hyperthermia-treated rats showed decreased DOX in the mean area under the concentration-time curve (AUC) and decreased plasma DOX t1/2 but increased plasma drug clearance. These heat-mediated alterations in DOX pharmacokinetic parameters, however, do not account for the significant increases in thermochemotherapy-mediated cytotoxicities observed in tumour, and in normal renal and cardiac tissues.

Animals↗

PubMedDate not supplied

Tissue distribution as a factor in species susceptibility to toxicity and hazard assessment. Example: methylmercury.

Data on the tissue distribution and pharmacokinetics of methylmercury(MeHg) in cats and humans were utilized as an example of how such data can assist in extrapolating toxicity data between animal species. These data demonstrate that the whole-body half-time for clearance of MeHg was the same for cats (76.2 +/- 1.6 days) and humans (78 +/- 5 days) and that the concentration of MeHg in the brain at comparable signs of toxicity were the same (10 ppm) in the two species. However, the blood:brain ratio of MeHg concentration was 10 times as high in cats (1:1) as humans (1:10). From these data it was hypothesised that the no-effect level of methylmercury intake in cats should be 10 times that for humans. This hypothesis was verified from data o MeHg toxicity in cats and humans which demonstrated that ataxia developed in cats at a minimum dose of 46 microgram MeHg/kg body wt/day with blood MeHg levels of 6 to 8 ppm; humans developed ataxia with blood MeHg levels of 0.6 to 0.8 ppm and an estimated intake of 4 microgram MeHg/kg body wt/day.

Animals↗

PubMedDate not supplied

Residualizing indium-111-radiolabel for plasmid DNA and its application to tissue distribution study.

To develop a suitable vector and an administration technique for in vivo gene transfer, the tissue distribution of plasmid DNA (pDNA) needs to be understood. In this study, a novel residualizing radiolabel for pDNA was developed. 4-[p-Azidosalicylamido]butylamine (ASBA) was coupled with diethylenetriaminepentaacetic acid (DTPA) anhydride, then the conjugate was reacted with pDNA by photoactivation, followed by labeling with [(111)In]InCl(3) to obtain (111)In-pDNA. The overall structure of pDNA was well preserved, and the retention of its transcriptional activity was 40-98%. After intravenous injection of (111)In-pDNA into mice, about 50% of the radioactivity was recovered in the liver within 3 min. The level remained stable for at least 2 h, followed by a very slow decrease to 45% at 24 h. This contrasted with the results obtained with (32)P-pDNA by nick translation, in which a rapid decrease in hepatic radioactivity was observed. The amount of radioactivity in the lung following the administration of polyethyleneimine/(111)In-pDNA complexes correlates well with the transgene expression. These results indicate that the novel residualizing radiolabel clearly demonstrates the cells that have taken up pDNA and, therefore, gives us useful information about how to design a better approach for nonviral in vivo gene delivery.

Animals↗

PubMed1988

Physical training and changes in regional adipose tissue distribution.

Obesity has been associated with numerous metabolic complications, such as changes in the concentration and/or composition of plasma lipoproteins, glucose intolerance and hyperinsulinemia leading to diabetes and hypertension. The relation of obesity to cardiovascular disease has not, however, been consistently reported. Recent prospective studies have clearly indicated that the distribution of adipose tissue was a significant cardiovascular risk factor and numerous studies have shown that metabolic disturbances were more closely associated with the level of abdominal fat than excess adiposity per se. As obese men generally store their energy excess in the abdominal region and women in the peripheral fat depots, the metabolic complications of obesity seem to be more closely related to adiposity in men than in women. It is suggested that the sex dimorphism observed in adipose tissue localization could partly explain the greater cardiovascular risk associated with obesity in men than in women. Indeed, obese women with a "male" (abdominal) distribution of body fat have greater metabolic complications than women with lower body fat. When aerobic exercise-training is used to induce weight loss, men generally lose more fat than women. In men, the loss of adipose tissue appears to be central, potentially reducing the risk of cardiovascular disease, whereas a relative resistance to fat loss is observed in women compared to men. Although resistance to fat loss is noted in women, those with a "male" distribution of adipose tissue (high waist-to-hip ratio and high intra-abdominal fat deposition) and with associated metabolic complications greatly benefit from aerobic exercise-training.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗

PubMed1990

Effects of dietary and intraperitoneally administered beta-naphthoflavone on mutagenicity and tissue distribution of Trp-P-1 in the rat.

The effect of dietary beta-naphthoflavone (BNF) on tissue retention of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was studied in the rat. Female rats, 3 weeks old, were fed a BNF-containing diet for 3 days before being dosed orally or i.v. with 14C-labelled Trp-P-1. The rats were killed at 4, 24 or 48 h after dosage and subjected to tape-section autoradiography. The tissue localization of Trp-P-1-derived radioactivity was compared to that observed in untreated rats and in rats given BNF i.p. Ethoxyresorufin-O-deethylase (EROD) activity and mutagenicity of Trp-P-1 in the Ames test, using S9 prepared from forestomach, glandular stomach, small intestine, liver and lung, were used as in vitro assays to measure the degree of cytochrome P450IA1 and/or P450IA2 induction. Dietary BNF treatment caused a 30- to 40-fold increase in EROD activity in the small intestine, but only a 2-fold increase in the liver and the lung. These inter-organ differences were not observed after i.p. administration of BNF. The increase in mutagenicity of Trp-P-1 in the Ames test could be correlated to the increase in EROD activity. The autoradiographic data showed that the route of administration of BNF as well as of Trp-P-1 were important for the tissue localization of Trp-P-1. Dietary BNF treatment caused a pronounced retention of Trp-P-1-derived radioactivity in the epithelia of the small intestine, forestomach, oesophagus and the oral cavity, regardless of the administration route of Trp-P-1; a similar though less pronounced epithelial retention was observed after i.p. injection of BNF. A clear-cut boundary of accumulated radioactivity between the forestomach and the glandular stomach where the levels were almost non-detectable was observed in rats fed the BNF-containing diet. It is concluded that dietary inducers may be important determinants of metabolism and tissue distribution of toxic compounds.

Animals↗

PubMed1990

ANF disappearance and tissue distribution in rats.

The disappearance of [125I]atrial natriuretic factor (ANF; Ser99-Tyr126) from the circulation and its tissue distribution with or without nonlabeled ANF pretreatment were investigated in normotensive Sprague-Dawley rats. Preadministration of the cold peptide increased plasma radioactivity levels for over 8 min following labeled ANF injection but did not change the half-life of circulating labeled ANF. The metabolic clearance rate (MCR) and volume of distribution in the first, second, and steady state phase were significantly decreased after cold ANF pretreatment. Circulating iodo-labeled ANF was taken up by several organs, even by tissues such as fat or bone, but its urinary excretion was very low. The highest uptake was found in the liver (16 +/- 1% of the injected dose), lung (14 +/- 1%), and kidney (12 +/- 1%), diminishing by 21, 89, and 59%, respectively, after cold ANF preinjection. The brain radioactivity was negligible implying an inability of [125I]ANF to cross the blood-brain barrier. Our data underscore the importance of the uptake-mediated, cold ANF preadministration suppressible clearance of ANF from the circulation, probably one of its basic elimination mechanisms. The liver, lung, and kidney are probably the most important participants in the MCR of ANF.

Animals↗

PubMed1998

Cloning and tissue distribution of two new potassium channel alpha-subunits from rat brain.

The expressed sequence tag (EST) database is a valuable tool to identify functionally related clones, when sequence similarity is so low that standard library screening methods cannot be successfully applied. Comparing conserved protein sequences of cloned voltage-gated potassium channels led to the identification and cloning of a new putative potassium channel alpha-subunit from rat brain, Kv9.1. A homologue of this alpha-subunit was also found in human brain tissue. A second alpha-subunit, Kv9.3, most probably belonging to the same subfamily, was also isolated and sequenced. Tissue distribution and analysis of genomic DNA were performed for both channels. rKv9.1 is expressed exclusively in the central nervous system, whereas rKv9.3 shows a widespread tissue distribution. No currents could be measured in X. oocytes upon injection of rKv9.1 or rKv9.3 cRNA.

Amino Acid Sequence↗

PubMed2006

Interconversion and tissue distribution of pentoxifylline and lisofylline in mice.

The aim of this study was to assess the interconversion pharmacokinetics and tissue distribution of pentoxifylline and the active (R)-enantiomer of its metabolite M1, lisofylline in male CD-1 mice. Both compounds were administered intravenously at a dose of 50 mg/kg on two separate occasions. Serum and tissues were collected at different time points following drug administration. In addition, the (S)-enantiomer of M1 was administered to a group of mice and serum samples were obtained. Analyte concentrations were measured by chiral HPLC. All serum concentration versus time data were fitted simultaneously to a pharmacokinetic model incorporating interconversion processes of parent drug and metabolites. The estimated conversion clearance of (-)-(R)-M1 to pentoxifylline (CL21) was six times greater than that for the reverse process (CL12). The interconversion of pentoxifylline and (+)-(S)-M1 was faster as reflected by the values of conversion clearances CL13 and CL31 which were approximately 16 and 7 times greater in comparison with the corresponding clearances for the interconversion of pentoxifylline and (-)-(R)-M1. When fitting pharmacokinetic data of both parent compounds to a one-compartment model, the values of elimination clearances assessed were close to those obtained on the basis of the interconversion model. After administration of pentoxifylline, tissue-to-serum AUC ratios ranged from 0.1 for liver and lungs to 0.32 for brain tissue. Serum levels of its metabolite, (-)-(R)-M1 were very low, whereas its tissue levels exceeded serum concentrations. The highest value of metabolite-to-parent AUC ratio (4.98) was observed in lungs. When (-)-(R)-M1 was given as a parent drug, tissue-to-serum AUC ratios in liver, kidney, and lungs were very close and ranged from 0.64 to 0.72. At the same time, levels of its metabolite, pentoxifylline were relatively low both in serum and all tissues studied. In consequence, metabolite-to-parent AUC ratios did not exceed the value of 0.27. In conclusion, reversible metabolism plays a modest role in the disposition of pentoxifylline and (-)-(R)-M1. It seems that pentoxifylline has less favourable pharmacokinetic properties than (-)-(R)-M1 due to lower concentrations attained in target organs. High levels of (-)-(R)-M1 observed after pentoxifylline administration in certain tissues such as liver or lungs suggest that pentoxifylline may constitute an effective prodrug for (-)-(R)-M1 in these organs.

Animals↗

PubMed2004

Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat.

The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible acetylcholinesterase inhibitor, were studied in male and female non-pregnant and pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most studies were performed using 3H-labelled galantamine hydrobromide, measuring unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by high-performance liquid chromatography (HPLC), liquid scintillation counting and quantitative whole-body autoradiography (QWBA). Plasma levels after single intravenous administration of UD (1.25-2.5 mg/kg) declined bi- or triphasically, with an elimination half-life of 3.5 h in male, and 5.1 h in female rats. The plasma clearance (Cl) averaged 1.9 l/kg/h (male rats) and 0.9 l/kg/h (female rats), and the volume of distribution (VdSS) was about 5 l/kg for both male and female rats. Following oral administration (2.5-10 mg/kg), galantamine was rapidly absorbed in both sexes, with an absolute oral bioavailability of 77%. Distribution studies after oral administration of 3H-galantamine showed an almost immediate equilibrium between plasma and tissues, with highest tissue levels of NVR and UD in liver, kidney, salivary glands, adrenal glands and, for the female rat, spleen, and lowest in white fat. To most tissues and especially to brain, the distribution of UD was more pronounced than that of its metabolites. Tissue concentrations of UD and NVR declined at a similar rate as plasma, showing no undue retention. QWBA in the pigmented rat showed the same distribution and elimination pattern of NVR. Only in hair follicles and choroid some retention of NVR was seen, but the calculated half-life was less than one day. In the female pregnant SPF Wistar rat, maternal tissue distribution of NVR was similar to that of the non-pregnant rat. NVR tissue levels in the foetus were similar to those found in maternal blood during the whole experiment, indicating a rapid equilibrium without accumulation.

Administration, Oral↗

PubMedDate not supplied

Tissue distribution and excretion of radioactively labelled compounds in the Wistar rat after administration of [N-methyl-14C]-erythromycin A.

Tissue distribution and excretion of radioactively labelled compounds was studied in the Wistar rat after i.v. administration of [N-methyl-14C]-erythromycin A. Whole-body autoradiography and liquid scintillation counting was used to investigate the tissue localization of radioactivity in pregnant and non-pregnant rats. Tissue levels were maximal within 20 min, except for lachrymal glands, thymus and brain. Large amounts of radioactively labelled compounds, partly originating from active secretion, were present in the small intestine and caecum. Marked concentration of radioactively labelled compounds was also observed in the liver, spleen, lachrymal and salivary glands, lymph nodes, mammary glands, skin, bone marrow, and, to a lesser extent, in the lung, kidney and skeletal muscle. During six hours of experimental follow-up, plasma levels remained lower than corresponding tissue levels. At 1 h the radioactivity in fetuses was about three times lower than that in maternal blood. Within 48 h, more than 90% of the administered radioactivity was excreted. The amounts of radioactivity recovered in urine, faeces and expired air were about 19%, 48% and 24% respectively. After 48 h, 8% of the administered radioactivity was found in the carcass.

Animals↗