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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↗

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↗

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↗

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↗

PubMed1991

Adipose tissue distribution and function.

Adipose tissue distribution in man is dependent on genetic and environmental factors. The total and regional masses of adipose tissue are dependent on the number of adipocytes as well as their degree of filling with depot fat. Currently available evidence does not suggest a specific regional regulation of fat cell multiplication in subcutaneous depots, which instead seems to occur at a certain critical degree of filling of available adipocytes. The control of the rate of filling of adipocytes then seems to be the main factor determining the local, regional mass of adipose tissue. This in turn is regulated by the balance between the lipid accumulating and mobilization processes. The steroid hormones exert major permissive effects on these processes. It seems likely that the resulting effect of the rate of secretion of various steroid hormones, and the local density of their specific receptors, decide the regional distribution of body fat. Physiological and clinical situations with defined differences in these regulatory factors would then be expected to have characteristically different adipose tissue distribution. Sex differences include a larger subcutaneous adipose tissue in women than men, explainable at least partly by a depot in the gluteal-femoral region in women, which is essentially absent in non-obese men. Men on the other hand seem to have a larger proportion of their adipose tissue organ localized intra-abdominally. In addition, the gluteal-femoral fat cells are specifically enlarged in women, and have a higher lipoprotein lipase activity. While the larger adipose tissue in non-obese women may well be genetically linked, the specific characteristics of the gluteal-femoral adipocytes are most likely regulated by female sex steroid hormones. Another apparent sex difference is the ability of women to protect visceral depots from fat accumulation up to a certain degree of obesity, while men deposit excess fat in this region in parallel with other depots. This might, at least partly, simply be explainable by the smaller 'available space' in male than female adipose tissue. It should be emphasized that the effects of sex steroid hormones on the regulation of adipocyte metabolism occur only in concert with cortisol, which is always present. Cortisol itself expresses lipoprotein lipase activity as well as beta-adrenergic receptors (BARs), and probably has additional effects, not yet revealed. The net effect seems, however, to be lipid accumulation as seen in the apparently glucocorticoid receptor (GR) dense visceral adipose tissue in conditions of glucocorticoid excess, such as Cushing's syndrome. The effects of the sex steroid hormones should be regarded against this background.(ABSTRACT TRUNCATED AT 400 WORDS)

Abdomen↗

PubMed1991

Mean residence times and distribution volumes for drugs undergoing linear reversible metabolism and tissue distribution and linear or nonlinear elimination from the central compartments.

Equations for the mean residence times in the body (MRT) and in the central compartment (MRTc) are derived for bolus central dosing of a drug and its metabolite which undergo linear tissue distribution and linear reversible metabolism but are eliminated either linearly or nonlinearly (Michaelis-Menten kinetics) from the central compartments. In addition, a new approach to calculate the steady-state volumes of distribution for nonlinear systems (reversible or nonreversible) is proposed based on disposition decomposition analysis. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.

Computer Simulation↗

PubMedDate not supplied

Tissue distribution of propafenone in the rat after intravenous administration.

Tissue distribution of propafenone has been studied in the rat. Measurement of propafenone was made in several tissues: plasma, heart, kidney, lung, liver, muscle, fat and brain, after i.v. administration of 2 mg/kg of the drug. The plasma propafenone kinetics profile can be described by a two-compartmental model. The pharmacokinetic parameters, derived from plasma levels, showed a t1/2 beta of 55.4 min, the central Vd/kg of 2.4 ml/kg, the Cl of 62.8 ml/min.kg and the AUC0-oo of 31.6 micrograms.min/ml. The analysis of the propafenone tissue distribution showed the highest concentration of drug in the lung, followed by the heart and kidneys. A significant concentration was found in brain, muscle and adipose tissue, with concentration ratios (tissue/plasma) above 1. The half-life values obtained for individual organs and tissues are similar to those obtained in plasma, around 1 h. In the post-distributive phase, plasma and tissue concentrations decline in parallel.

Animals↗

PubMed1979

Tissue distribution of brain-thymus shared antigens recognized by anti-brain xenosera in the rat, dog and man.

A comparative and quantitative study of the tissue distribution of brain-thymus shared antigens was carried out using rabbit antisera to rat, dog and human brain homogenates, assayed on rat, dog and human thymus cells, respectively. Quantitative absorption analyses with eleven different tissues showed that the tissue distribution of the brain-thymus antigens was strikingly different in the three species. In the rat, the antigens were present in large amounts on both brain and thymus, to a lesser extent on bone marrow cells, but not at all, or only slightly, on the other tissues studied. In the dog, the shared antigens were present in large amounts only on brain. They were present in smaller amounts (approximately 5% compared with brain) on thymus, spleen, lymph node and, unexpectedly, kidney, and to a slight extent on bone marrow cells. In both rat and dog, absorption to a plateau with liver indicated the presence of brain-thymus shared antigens of restricted tissue distribution. No brain-thymus antigens of restricted tissue distribution could be detected in man, since liver, heart, kidney, brain and all other tissue studied, excepting erythrocytes and platelets, could absorb out all the antibody.

Animals↗

PubMed1992

Kinetic modeling of ouabain tissue distribution based on slow and saturable binding to Na,K-ATPase.

The significance of the binding to Na,K-ATPase in the tissue distribution of ouabain was previously documented (Harashima et al., Pharm. Res. 9:474-479, 1992). The purpose of this study was to obtain a kinetic model of ouabain tissue distribution. In most tissues, the ouabain concentration continued to rise after the termination of infusion (5 min), with the peak tissue concentration at approximately 20 min. This delay could not be explained by the rapid equilibrium model (RE model), nor could the kinetics of ouabain be explained by an RE model modified for saturable binding. Since ouabain binding to Na,K-ATPase is slow, the association and dissociation processes were incorporated into a model that can accurately fit the observed time courses of ouabain. The obtained binding parameters corresponded well with the observed values in the in vitro binding experiments, except for muscle. These results quantitatively support the role of the slow and saturable binding of ouabain to Na,K-ATPase in its tissue distribution.

Animals↗

PubMedDate not supplied

Tissue distribution and metabolic disposition of zidovudine in rats.

The tissue distribution and metabolic fate of [5'-3H]zidovudine was studied in rats after a single dose of 10 mg/kg by gavage. The drug was absorbed rapidly and distributed into all tissues. Peak blood and tissue levels were observed 0.25 hr post-dose. The level of peak radioactivity in the stomach, intestine, liver, spleen, adrenals, and kidney was higher than in plasma, while in the heart, lung, thymus, lymph nodes, muscle, bone, and skin it was similar to that in plasma. Only in the testes and the brain the radioactivity was lower than in plasma. Blood and plasma radioactivity levels were nearly equivalent. A biphasic disappearance of radioactive material was observed in blood and plasma, as well as in most tissues, with a rapid decline in the early phase (0.25-4 hr) and a slower decline thereafter. The 0-24-hr urinary and fecal recoveries (mean +/- SD) of radioactive material were 78 +/- 14% and 20 +/- 9% of dose, respectively, indicating virtually complete recovery of the radioactive dose. Reversed-phase HPLC analysis indicated that approximately 88% of urinary radioactivity corresponded to unchanged zidovudine, with the remaining radioactivity accounted for by five metabolites. One of these urinary metabolites was identified as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine and another as 3'-amino-3'-deoxythymidine (AMT). The majority of fecal radioactivity (greater than 70%) corresponded to AMT. There is a component of biliary excretion in the disposition of zidovudine. At least 7% of a parenteral dose of zidovudine was secreted in the bile, primarily as 3'-azido-3'-deoxy-5'-beta-D-glucuronylazidothymidine, which may be a source of fecal AMT.

Animals↗

PubMed1992

Significance of binding to Na,K-ATPase in the tissue distribution of ouabain in guinea pigs.

Ouabain binds specifically to Na,K-ATPase on the plasma membrane and therefore serves to measure the tissue concentration of Na,K-ATPase. We examined the role of ouabain binding to Na,K-ATPase in its overall tissue distribution. The tissue-to-plasma concentration ratio (Kp,vivo) was defined in each tissue after intravenous administration of 3H-ouabain in guinea pigs, and specific binding of ouabain to Na,K-ATPase was measured in tissue homogenate to obtain the dissociation constant and binding capacity in each tissue. A predicted tissue-to-plasma concentration ratio (Kp,vitro) was calculated using the obtained binding parameters and the volume of extracellular space in each tissue. The absolute values of Kp,vitro were comparable to those of Kp,vivo, except in brain. Regression analysis showed that the specific binding capacity of Na,K-ATPase in each tissue is the main factor in the tissue variation of Kp,vivo. Therefore, the binding of ouabain to Na,K-ATPase plays a significant role in the tissue distribution of ouabain.

Algorithms↗

PubMed1991

Metabolic behaviour and tissue distribution of nalidixic acid in chickens.

The metabolic behaviour and tissue distribution of nalidixic acid in normal and E. coli infected chickens were carried out using spectrofluorimetric and microbiological techniques following a single and multiple oral administration of 25 mg/kg b. wt. The obtained results revealed that free nalidixic acid (free NA) is the major fraction of the total drug concentration in serum, liver and kidneys. The free active nalidixic acid was in a higher concentration than hydroxynalidixic acid (free HNA) and both conjugates of NA and HNA following single and multiple oral administration. The obtained results showed that nalidixic acid was highly distributed in all tissues in normal and E. coli infected chickens, with the highest concentrations in kidneys, liver and heart and lowest concentrations in brain, muscles and intestine following oral administration of 25 mg/kg b. wt. twice daily for 5 successive days. Spectrofluorimetic technique was more sensitive for nalidixic acid determination than microbiological method. Nalidixic acid revealed longer withdrawal time in diseased chickens than in normal chickens.

Animals↗

PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 2nd communication: tissue distribution and whole-body autoradiography of imidapril in rats.

Tissue distribution, whole-body autoradiography and metabolic profiles in selected tissues of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) were studied in male and female rats after oral and intravenous administration of [N-methyl-14C]-imidapril (1 and 5 mg/kg) or [alanine-3-14C]-imidapril (1 mg/kg). After oral administration of [N-methyl-14C]-imidapril, radioactivity was distributed relatively rapidly to all tissues, except for the central nervous system. Maximum concentrations in most tissues were observed at 30 min to 1 h after dosing. Concentrations greater than those in the plasma were found in the liver, kidney and particularly in the lung except for the gastrointestinal contents. The elimination from the lung was relatively slow (t1/2: ca. 28 h). At 96 h after dosing, there was no evidence of remaining radioactivity in any tissues, except for the lung and kidney. No gender-related differences in the tissue distribution profile of radioactivity were observed in the whole-body autoradiogram. After intravenous administration, the distribution pattern of radioactivity was similar to the results of oral administration, except for the gastrointestinal contents. There was no specific binding of drug-related compounds to melanin-containing tissues such as the hair follicles and the uveal tract of the eye in the pigmented rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1979

Identification and unusual tissue distribution of the canine and human homologues of Thy-1 (theta).

The tissue distribution of the canine and human homologues of Thy-1 were studied using quantitative absorption analyses of liver absorbed anti-brain xenosera assayed on thymus cells. Cross-reactivity studies with pure rat Thy-1 established that the assays were detecting the homologues of rat Thy-1. The results showed that the tissue distribution of Thy-1 varies remarkably between species. Canine Thy-1 was found in large amounts only on adult brain. It was present in much smaller amounts on thymus (8% compared with brain), and was also found on lymph node, spleen and bone marrow (3, 1 and 0.5%, respectively, compared with brain). Surprisingly, it was found on kidney in amounts equal to that on thymus. Studies with the fluorescence-activated cell sorter established that canine Thy-1 was present on all thymocytes and peripheral T lymphocytes. Neonatal thymus and kidney had adult levels of Thy-1, but only small amounts of Thy-1 were present on neonatal brain. In man, brain was again the only tissue to contain large amounts of Thy-1. Surprisingly, it was absent from human thymus, and present on human kidney in amounts roughly equivalent to that seen in the dog. It was absent from spleen, lymph node, bone marrow, liver, heart, erythrocytes, platelets, and serum. Cross-reactivity studies showed that dog and human Thy-1 showed extensive serological cross-reaction, and that the dog-rat and human-rat cross-reactive components were identical.

Animals↗

PubMed1975

Distribution of an adenohypophysial constituent in the body. II. Quantitative tissue distribution in the rat.

A peptide with a molecular weight of about 5000 has previously been shown to affect the output of semen in frogs and probably also in mammals. This sperm-releasing substance is not part of any known gonadotropic hormone. The tissue distribution of this substance has been investigated. The iodinated substance has been injected into rats and the radioactivity content of the different tissues has been determined. Iodinated rat albumin has been injected into other rats, to determine the content of blood in the different tissues. A formula has been derived to obtain a figure for real accumulation, using the radioacitivity content of the blood and of the tissues after injection of the sperm-releasing substance and albumin, respectively. The sperm-releasing substance is incorporated into the adenohypophysis, neurohypophysis, liver, kidney, lung, ovary, uterus and some male sexual organs. The causes for this distribution are discussed.

Animals↗

PubMed1979

Tissue distribution and excretion of 14c-styrene in male and female rats.

The tissue distribution and excretion of an oral dose of 20 mg/kg of 14C-styrene was studied in both male and female rats at various time intervals after administration. Peak tissue levels were attained at or before 4 hours post administration. The organ with the highest concentration of radioactivity per unit weight was the kidney, followed, in order of decreasing concentration, by the liver and the pancreas. The data suggest a relationship between tissue distribution and kidney and liver toxicity. The high levels also found in the pancreas may bear some relationship to the reported increase in glucose tolerance in workers exposed to styrene. The principal route of excretion was via the kidneys, with 90% of the dose appearing in the urine within 24 hours of administration. Less than 2% of the dose was recovered from the feces.

Animals↗

PubMed1977

Nocardicin A, a new monocyclic beta-lactam antibiotic VI. Absorption, excretion and tissue distribution in animals.

The absorption, excretion and tissue distribution of nocardicin A, a new monocyclic beta-lactam antibiotic, were studied in various animals. When nocardicin A was given intramuscularly in single doses of 20 mg/kg to rats, rabbits, and dogs, the peak serum levels of nocardicin A were about 1.6 similar to 2.8 times higher than those of carbenicillin in all animals though the levels varied among the species tested. The serum half-life of nocardicin A in these animals was about twice that of carbenicillin. The 24-hour urinary recovery rate of nocardicin A after intramuscular injection was 68.5 percent in rabbits and 77.0 percent in dogs, but was low in rats; i.e., 0.7 percent. When nocardicin A was given intravenously in single doses of 20 mg/kg to these animals, the peak serum levels varied widely among the test species; i.e. about 3 times higher than those of carbenicillin in rabbits and dogs, similar to those in rats. The peak serum and tissue levels of nocardicin A after intramuscular to intravenous injection were the highest in the kidneys, followed by the liver, serum, lungs, heart and spleen. The levels in the liver were prolonged. Nocardicin A, and traces of unknown substances less active than nocardicin A were observed as active substances in the urine recovered after injection of nocardicin A.

Administration, Oral↗

PubMed1976

Phencyclidine: tissue distribution in the rat.

This study was performed to provide knowledge of the tissue distribution of phencyclidine and has demonstrated the lipophilic nature of the drug. The distribution of phencyclidine in blood, brain, and adipose tissue of rats has been determined at various time intervals during a 48-hr period. The affinity of phencyclidine for adipose tissue and the demonstration of the presence of this drug in brain tissue long after it is no longer detectable in blood provides some correlation between the tissue distribution of phencyclidine and its clinical manifestations occuring 24-48 hr after administration.

Adipose Tissue↗