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Biomedical subjects

J Hirate

Publications and source records attributed to J Hirate.

At least 19 recordsLinked to original sources
PubMed1995

Distribution of 1,25-dihydroxyvitamin D3[22-oxa] in vivo receptor binding in adult and developing skin.

Because of the therapeutic potential of oxacalcitriol (OCT, 22-oxa-dihydroxyvitamin D3), in vivo studies were conducted in adult and neonatal rats to identify the nuclear receptor sites of action in different tissues of the skin. Results were compared with those for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and oestradiol from previous studies. Autoradiograms were prepared from the dorsal skin of adult rats and the skin of the leg and head regions of neonatal rats 1 or 2 h after the injection of 3H-OCT. Specific nuclear concentrations of radioactivity, eliminated by competition with unlabelled OCT or 1,25(OH)2D3, were found in cells of the epidermis, outer hair sheath, hair bulb and sebaceous glands, but were absent or low in most fibroblasts of the dermis and hypodermis. The strongest nuclear binding of OCT was conspicuous in outer hair sheaths, where it was 1.5 to 3.2 times higher than in keratinocytes of the epidermis. The distribution of nuclear receptors for OCT was similar to that for 1,25(OH)2D3 but in part dissimilar to that for oestradiol. Oestradiol binding was found in the epidermis and hair sheaths, and also predominantly in fibroblasts of the dermis and hair dermal papillae. The results suggest genomic regulatory effects of OCT, similar to the effects of vitamin D, on proliferation, differentiation and activity of keratinocytes, growth and maintenance of hair, and proliferation and secretion of sebaceous glands. This may be utilized therapeutically, since OCT has a lower calcaemic effect than 1,25(OH)2D3.

Animals↗
PubMed1995

Nuclear receptors for 1,25-dihydroxy-22-oxavitamin D3 (OCT) and 1,25-dihydroxyvitamin D3 in gastric gland neck mucous cells and gastrin enteroendocrine cells.

22-Oxacalcitriol the analog with low calcemic effect and the original hormone 1,25(OH)2 vitamin D3 were localized by autoradiography in mouse stomach at different time intervals after intravenous injection. Both compounds showed a distinct nuclear concentration and retention in neck mucous cells of gastric and pyloric glands, and in dispersed endocrine cells in the antrum region. When the nuclear binding of radioactively labelled compound was compared between gastric neck cells and duodenal absorptive cells, binding was low but sustained in neck cells. Peak uptake after the injection was between 8 and 12 h in neck cells, but between 15 min and 30 min in duodenal villous epithelium. In the duodenum, weak nuclear labelling appeared at 8 h and was undetectable at 12 h under the conditions of the experiment. Nuclear labelling of neck cells remained detectable at 12 h and even after 24 h, similarly for both OCT and 1,25(OH)2 vitamin D3. These results suggest that the stomach is an important target tissue for vitamin D and its analog OCT. Regulation of neck cell functions is suggested, such as proliferation and differentiation of surface epithelium and gastric gland epithelium, and neck cell secretion of acidic mucus. Regulation is also indicated of G-cell gastrin secretion associated with gastrin paracrine effects on parietal cell HCl and intrinsic factor secretion, chief cell pepsinogen secretion, neck cell proliferation, as well as endocrine effects on systemic calcium homeostasis.

Animals↗
PubMed1994

1,25-Dihydroxyvitamin D3 and 22-oxa-1,25-dihydroxyvitamin D3 in vivo nuclear receptor binding in developing bone during endochondral and intramembranous ossification.

Target cells for 3H-labeled 1 alpha, 25(OH)2 vitamin D3 [1,25(OH)2D3, vitamin D] and its analog 3H-labeled 22-oxa-1 alpha, 25(OH)2 vitamin D3 (OCT) have been identified during endochondral and intramembranous ossification in developing, undecalcified, unembedded bone, using thaw-mount autoradiography. Two-day-old neonatal rats were injected with [3H]1,25(OH)2D3 or [3H]OCT; after 2 h leg, spine, and head were frozen and sectioned. In the epiphyseal-metaphyseal region specific nuclear concentrations of [3H]1,25(OH)2D3 and [3H]OCT were observed in identical cell populations, being low in cells of the articular and resting zone, intermediate in the proliferating zone, and highest in hypertrophic chondrocytes and in osteoblasts and precursor cells. In the primary spongiosa intertrabecular spaces there were a large number of cells with nuclear labeling--probably osteoblasts and precursor cells. In contrast, in the secondary spongiosa intertrabecular spaces, apparent blood-forming cells were mostly unlabeled. Osteoblasts along bone spicules and compact bone in long bones, vertebrae, and head also showed strong nuclear labeling, as did cells of the periosteum. These data suggest that 1,25(OH)2D3 and OCT regulate development, differentiation, and activities of chondrocytes and osteoblasts, including differentiation of resting chondrocytes into proliferating and hypertrophic chondrocytes that involve "chondroclastic" enlargement of lacunae and "trans-differentiation" of surviving hypertrophic chondrocytes; differentiation of stroma cells into osteoblasts; and in periosteum and other regions of intramembranous ossification differentiation of precursor cells and osteoblasts. Nuclear receptor binding and their selective and hierarchical distribution during cell differentiation appear to correspond to multiple genomic effects toward growth, regeneration and repair. The findings indicate a physiological significance and therapeutic potential of 1,25(OH)2D3 and in particular of its less hypercalcemic analog OCT.

Animals↗
PubMed1991

Age-dependent changes in first-pass metabolism of acetaminophen in rats.

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first-pass metabolism of acetaminophen was examined using 3-week-old, 10-week-old and 1-year-old rats after administration of 30 mg kg-1 doses by intra-arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10-week-old and 1-year-old rats (Eo = 0.46) and the major contribution to the overall first-pass metabolism was due to the GIT (Eg = 0.50-0.53). Oral extraction in 3-week-old rats was minimal (Eo = 0.10) and there did not appear to be an extraction by the GIT (Eg = 0.00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first-pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3-week-old) and 10-week-old rats were similar after drug administration by the intra-arterial and intravenous routes.

Acetaminophen↗
PubMed1991

[First-pass metabolism of acetaminophen in thyroxine treated rats].

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.

Acetaminophen↗
PubMed1990

First-pass metabolism of acetaminophen in rats after low and high doses.

The first-pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg-1 doses by intra-arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first-pass effect after oral administration (oral extraction) was extensive (Eo = 0.34-0.50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0.33-0.50). At higher doses (150 and 300 mg kg-1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose-dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.

Acetaminophen↗
PubMed1990

Disposition of phenytoin in analbuminemic rats.

The disposition characteristics of phenytoin were investigated in analbuminemic rats to study the effect of plasma protein binding on phenytoin disposition. Blood and plasma phenytoin concentration determinations, measurement of plasma protein phenytoin binding, and whole-body autoradiography were performed after intravenous bolus injection of 10 mg kg-1 of phenytoin. When plasma phenytoin was assayed, total body phenytoin clearance (CL) was faster and its apparent volume of distribution (Vd) greater in the analbuminemic rats in comparison to the controls. The plasma protein binding of phenytoin was significantly lower in the analbuminemic rats, suggesting the disposition characteristics of phenytoin were altered in the presence of low plasma albumin concentrations due to reduced plasma phenytoin protein binding. On the other hand, when blood phenytoin levels were analyzed, no difference in CL and a less pronounced difference in Vd were noted between the two groups of rats. The red blood cell-to-plasma phenytoin concentration ratios were greater in analbuminemic rats, suggesting that the distribution of phenytoin into red blood cells was greater in the mutant rats.

Animals↗
PubMed1989

Enhancement of phenytoin binding to tissues in rats by heat treatment.

Phenytoin binding to heat-treated tissue homogenates has been examined to characterize the phenytoin binding to tissues. The binding to the heat-treated tissue homogenates was enhanced in all tissues studied compared with controls. The heating might produce the changes in conformation of proteins in tissues and then enhance phenytoin binding to tissue homogenates.

Animals↗
PubMed1988

Factors causing age-dependent changes in phenytoin tissue and serum binding in rats.

The factors that cause age-dependent changes in phenytoin tissue and serum protein binding in rats were studied. It was confirmed that the age-dependent changes in the concentration of tissue constituents to which phenytoin bound mainly governed the change in phenytoin tissue binding. The concentration of the tissue constituents, protein and phospholipid, was changed by the water content in tissues in the growth process of rats. The increase in serum protein binding of phenytoin in the growth process of rats was caused by changes in both serum albumin concentration and binding parameters of phenytoin to serum albumin. The changes in binding parameters of phenytoin to serum albumin were led by those in the molar rations of free fatty acids to albumin.

Aging↗
PubMed1987

Age-dependent changes in phenytoin tissue distribution in rats.

Age-dependent changes of phenytoin disposition in rats were studied following intravenous administration of 5,5-[4-14C]-diphenylhydantoin to 1-d, 1-, 3- and 8-week-old rats. The distribution volumes changed similarly to those of warfarin in the growth process of rats. The lower clearances in infant and young rats were considered to be caused by the undeveloped liver function to metabolize phenytoin. The changes of distribution volumes in the growth process of rats were assumed to be based upon not only the changes in blood free fractions but also other factors. In any aged rats, the muscle largely contributed to the distribution of phenytoin in the body and the Kp values in the muscle decreased in the growth process of rats. This change of phenytoin transfer to the muscle affected the decrease of distribution volumes of phenytoin in 8-week-old rats and the distribution volumes of brain, lung and liver in infants and young rats were greater than those in adult rats. The Kp value in the lung in 8-week-old rats was smaller than the values in 1-d, 1- and 3-week-old rats and there was no significant difference in the Kp values in the liver among the 4 ages. These results were different from those in warfarin reported previously and suggested that warfarin and phenytoin bind different macromolecules in the liver and the lung.

Aging↗
PubMed1987

Age-dependent change in warfarin distribution volume in rats: effect of change in extracellular water volume.

The pharmacokinetics of insulin was studied following intravenous administration of 14C-inulin to 1-d, 1-, 3- and 8-week-old rats. The distribution volume of inulin varied 2-fold, from 689 ml/kg in 1-d-old rats to 340 ml/kg in 8-week-old rats in the growth process of rats. This result was similar to that of warfarin and there was a statistically significant correlation between the distribution volume of warfarin and inulin (r = 0.984, p less than 0.02). In the growth process of rats, the Kp values of warfarin in muscle, which play an important role in the distribution kinetics of warfarin changed in parallel with those of inulin. These results and pharmacokinetic considerations indicated that in warfarin, which is highly bound to serum protein and shows a small distribution volume, the change in the distribution volume in the growth process of rats following administration of a pharmacologically realistic dose (1 mg/kg) is led by the change in the extracellular volume of tissues and that the change in serum protein binding of warfarin might play a minor role in the change in the distribution volume in the growth process.

Aging↗
PubMed1987

Age-dependent changes in phenytoin tissue bindings in rats: comparison between in vivo and in vitro tissue-to-blood partition coefficients (Kp values) of phenytoin.

Age-dependent changes in phenytoin tissue bindings in rats were investigated by equilibrium dialysis using serum and 10% tissue (brain, lung, liver, kidney and muscle) homogenates. All percentages of phenytoin bound to serum and tissue homogenates were independent of the initial phenytoin concentration (2 to 25 micrograms/ml) in 1-d, 1-, 3- and 8-week-old rats. The percentages bound to serum, brain, liver, kidney and muscle in newborn rats (1-d-old rats) were lower than those in 8-week-old rats and the percentages bound increased gradually in the growth process. However, those in lungs were constant in all ages of rats. It was assumed that the age-dependent changes in phenytoin tissue binding were caused by the changes in the quantities of tissue constituents to which phenytoin bound in the growth process. Tissue-to-blood partition coefficients (Kp values) were calculated from in vitro tissue binding data and the pH-difference across the cell membrane. These Kp values were in good agreement with the in vivo Kp values reported previously. It was concluded that the age-dependent changes in phenytoin tissue distribution were caused by the age-dependent changes in phenytoin binding to blood constituents and tissues but that the change of phenytoin blood binding contributed to the age-dependent changes in Kp values of phenytoin more than to phenytoin tissue binding and consequently the Kp values of phenytoin decreased as rats grew.

Aging↗
PubMed1986

Age-dependent changes in warfarin tissue distribution.

Whole blood levels, serum protein binding and tissue concentration following intravenous administration of warfarin were investigated in 1-d-old, 1-, 3- and 8-week-old rats to determine the drug disposition in the growth process. It was shown that the clearance of warfarin in 1-d-old or 1-week-old rats was considerably lower than that in 3- or 8-week-old rats. The decrease in clearance in infant and young rats was considered to be caused by the immaturity of the physiological function of the liver to remove exogenous compounds. The distribution volume in 1-d-old or 1-week-old rats was larger than that in 3- or 8-old rats. The percentages of serum free warfarin in 1-d-old and 1-week-old rats were about twice those in 3- and 8-week-old rats. The increased distribution volume in infant rats was considered to be caused by a lower serum protein binding in these rats.

Aging↗
PubMed1986

Disposition of glycyrrhetic acid and its glycosides in healthy subjects and patients with pseudoaldosteronism.

As a first step to elucidate the disposition of traditional Chinese formulations which contain licorice, the disposition of plain licorice was investigated in humans. Glycyrrhetic acid (GLA) was measured by an enzyme immuno-antibody technique. Glycyrrhetic glycosides (GLA-GS), such as glycyrrhizin, were measured after acid hydrolysis to GLA by the enzyme immuno-antibody assay. Five normal subjects were orally administered a decoction of licorice containing 133 mg of glycyrrhizin. It was found that the time required for maximum serum concentration of GLA-GS was less than 4 h after the administration. Although there were large individual differences, it was found that GLA-GS was eliminated from the blood for the most part within 72 h. On the other hand, GLA reached maximum serum concentration at about 24 h after administration and in two of the five cases it was still detected in the blood even after 96 h. Urinary excretion of GLA was about 2% of the total dose of glycyrrhizin administered. This suggested that there were great differences among the subjects in the absorption and urinary excretion of GLA-GS. The serum GLA levels in two clinical cases who presented pseudoaldosteronism by licorice containing formulations were as high as 70-80 ng/ml, with GLA-GS levels being very low. This fact suggests that pseudoaldosteronism develops in association with GLA rather than with GLA-GS.

Aged↗
PubMed1985

The change of p-aminohippuric acid disposition kinetics accompanied by growth in mice.

The change of disposition kinetics for p-aminohippuric acid (PAH) was studied following intravenous administration of p-[glycyl-1-14C]aminohippuric acid to 1-day-old, 1-week-old, 3-week-old and 8-week-old mice. The expiratory excretion of 14CO2 in 24 h following the administration was almost negligible in 1-day-old and 1-week-old mice in contrast to 3-week-old (6.8 +/- 1.8%) and 8-week-old (8.8 +/- 1.9%) mice. The ability to metabolize PAH may not be developed in these infant mice. The elimination of blood radioactivity following the administration was considerably delayed in 1-day-old and 1-week-old mice, especially in 1-day-old mice, suggesting that the renal tubular secretory function for PAH might not have been developed in the infant mice. Whole-body autoradiographic data showed that the transfer of PAH from blood to muscle was enhanced in 1-day-old and 1-week-old mice, especially in 1-day-old mice, compared to 3-week-old and 8-week-old mice. The enhanced muscular cell membrane permeability to PAH in 1-day-old and 1-week-old mice was considered to be the most plausible explanation for this result.

Age Factors↗