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Biomedical subjects

R Hori

Publications and source records attributed to R Hori.

At least 109 records · Page 6Linked to original sources
PubMed1991

Moment analysis of drug disposition in kidney. VI: Assessment of in vivo transmembrane transport of p-aminohippurate in tubular epithelium.

This paper describes a novel method to assess the antiluminal membrane (ALM) and luminal membrane (LM) transport in vivo across renal tubular epithelial cells. The method is based upon a noncompartmental moment analysis of the plasma concentration and urinary excretion rate curves following renal artery injection. Quantitative relationships are represented between the noncompartmental parameters (clearance, volume of distribution, and the mean transit time) and the first-order rate constants associated with transmembrane transport processes. The in vivo transepithelial transport of [14C]p-aminohippurate (PAH) was examined using the rat kidney in the absence or presence of various plasma concentrations of unlabeled PAH, cefazolin, and methotrexate. The tubular secretion intrinsic clearance was reduced with an increase in the plasma concentration of concurrent unlabeled organic anions. The distribution volume of PAH in the kidney decreased in association with a decrease in the amount of PAH secreted, whereas the mean transepithelial (artery-to-lumen) transit time (Tcell) remained constant. These findings indicate that ALM transport is a capacity-limited process determining the amount of tubular secretion, and that LM transport is linear over the concentration range examined and independent of the amount of secretion. The contribution of ALM and LM transport to transcellular transport was first clarified in vivo. The present method will be useful for analyzing the transmembrane transport processes in vivo for highly diffusible substances in the kidney.

Animals↗
PubMed1991

Enhanced bioavailability of subcutaneously injected insulin by pretreatment with ointment containing protease inhibitors.

The present study was undertaken to develop an ointment preparation containing a protease inhibitor for stabilizing subcutaneously injected insulin. The ointment containing the protease inhibitor, gabexate mesilate or nafamostat mesilate, was applied to the skin around the insulin injection site. Three results were obtained. First, gabexate and nafamostat inhibited insulin degradation in subcutaneous tissue homogenates in vitro. Second, after application of gabexate or nafamostat ointment, an appreciable amount of gabexate or nafamostat appeared in the subcutaneous tissue of rats or hairless mice and their concentrations were comparable to those seen in the in vitro experiment. Third, insulin degradation at the subcutaneous injection site in the rat was depressed after pretreatment with gabexate or nafamostat ointment. Pretreatment with gabexate or nafamostat ointment increased the plasma immunoreactive insulin (IRI) levels and the hypoglycermic effect of insulin in healthy volunteers. These results indicate that gabexate or nafamostat ointments stabilize subcutaneously injected insulin.

Administration, Topical↗
PubMed1991

Moment analysis of drug disposition in rat kidney: role of basolateral membrane transport in renal transepithelial transport of p-aminohippurate.

The determining step in transepithelial transport of p-aminohippurate (PAH) in renal tubular secretion has been elucidated in the rat isolated perfused kidney. The method was based upon a multiple indicator dilution experiment and non-compartmental moment analysis. Single-pass dilution curves were obtained from venous and urinary effluents after simultaneous intra-arterial injections of Evans blue with albumin, [3H]inulin and [14C]PAH. Probenecid was used as a transport inhibitor and dissolved in both perfusate and injection solution. The urinary excretion of PAH decreased depending on the probenecid concentration, while that of inulin was not affected. No correlation was observed between the amount of secretion and the mean residence time of secreted PAH in renal epithelial cells (Tcell). Since Tcell ought to be affected by the rate of secretion from cells to lumen, it was suggested that the secretion rate was independent of the amount secreted. In contrast, the amount of PAH excreted via tubular secretion showed a linear correlation with the volume of distribution in the kidney and the apparent rate constant for tubular uptake of PAH. Since these kinetic parameters reflect the transport from blood into cells across the basolateral membranes of renal epithelial cells, the present results demonstrated that basolateral membrane transport is a determining step in the transcellular transport of PAH and that the major effect of probenecid is the inhibition of transport from blood into cells.

Animals↗
PubMed1991

Trans-stimulation effect on H(+)-organic cation antiport system in rat renal brush-border membranes.

Trans-stimulation effect on tetraethylammonium (an organic cation) transport was examined in rat renal brush-border membrane vesicles. The uptake of [14C]tetraethylammonium at pH 6.0-8.5 was stimulated by preloading the membrane vesicles with unlabeled tetraethylammonium. When the uptake was measured in preloaded membrane vesicles in the presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, stimulation was observed at high pH but not at low pH. These results suggest that the mechanisms of the trans-stimulation effect on organic cation transport are different depending on the pH. When pH is low, the trans-stimulation is due to generation of an outward H+ gradient, which in turn stimulates [14C]tetraethylammonium uptake by H(+)-[14C]tetraethylammonium exchange. In contrast, when pH is high, the stimulation is due to direct exchange of tetraethylammonium for [14C]tetraethylammonium.

Animals↗
PubMed1991

Regulation of epidermal growth factor receptors in rat gastric mucosa: effect of fasting and sialoadenectomy.

The effect of fasting and sialoadenectomy on the binding of human epidermal growth factor (hEGF), beta-urogastrone, to plasma membranes isolated from rat gastric mucosa was studied to investigate the physiological changes in gastric EGF receptors for developing hEGF as an anti-ulcer drug. The binding of [125I]hEGF to the gastric membranes was significantly decreased after 40 h of fasting. Maximal binding was decreased to 74% of the control value without alteration of the binding affinity (Kd = 0.42 and 0.44 nM for the control and fasting group, respectively). There was little change in the binding of [125I]insulin to the gastric plasma membranes in response to fasting. Removal of the submandibular glands did not decrease EGF binding to the gastric membranes. These results indicate that changes in EGF binding to its receptors occur on plasma membranes of the rat gastric mucosa depending on the nutrient state.

Animals↗
PubMed1991

Regulation of epidermal growth factor receptors in rat gastric mucosa: effect of gastric ulceration.

The effect of experimental ulcers on the binding of human epidermal growth factor (hEGF), beta-urogastrone, to plasma membranes isolated from rat gastric mucosa was studied in order to develop hEGF as an anti-ulcer drug. The binding of [125I]hEGF to the gastric plasma membranes was significantly decreased 1 h after treatment with aspirin (300 mg/kg) and after 12 h of water-immersion stress. However, the number of EGF binding sites was increased 12 h after aspirin administration. There was little change in the binding of [125I]insulin to the gastric plasma membranes in response to water-immersion stress. These results indicate that changes in EGF binding to its receptors occur on plasma membranes of the rat gastric mucosa during ulcer.

Animals↗
PubMed1991

Pulmonary and hepatic disposition of hippuryl-L-histidyl-L-leucine.

The pulmonary and hepatic clearances of the synthesized angiotensin converting enzyme (ACE) substrate, hippuryl-L-histidyl-L-leucine (HHL) were evaluated by applying the multiple sites of input method and the recirculation pharmacokinetic model. Rats received a constant rate infusion via the carotid artery, jugular vein or portal vein in the absence or presence of the ACE inhibitor, captopril. Blood samples were collected from the femoral artery. The organ extraction ratio was calculated from the steady-state plasma concentrations and the mean organ transit time was computed as the difference in the mean residence times for various administration routes. Pronounced elimination in the lung and liver was observed in the absence of captopril. Pulmonary metabolism was completely depressed in the presence of captopril while the hepatic elimination was little affected. This suggests that the pulmonary elimination was entirely ascribed to ACE while there exists an alternative elimination process in the liver. The mean cardiopulmonary transit time was very short, indicating the pulmonary elimination of HHL may take place on the surface of the vascular endothelium. The evaluation of the pulmonary elimination of HHL described in this paper indicates a simple in vivo method for assessing the pharmacological effect of ACE inhibitors. The present pharmacokinetic approach will be useful for the quantification of drug disposition in individual organs in vivo.

Animals↗
PubMed1991

[The early changes in bone mineral metabolism due to radiation--measurement of bone mineral density in lumbar vertebra by quantitative computed tomography].

Osteosclerosis, osteonecrosis and compression fracture are commonly observed several years after radiation. Since lumbago usually occurs several months after radiation, the possibility that bone mineral metabolism is disturbed during and immediately after radiation cannot be ruled out. However, there have been no reports concerning early changes in bone mineral metabolism due to radiation. The bone mineral density was measured by QCT (Quantitative Computed Tomography) in 30 normal non-radiated cases and 14 radiated cases to investigate the changes in bone mineral metabolism due to radiation. The bone mineral density (QCT-Value: QCT-V) in the 3rd lumbar vertebra (L3) of normal non-radiated subjects decreased linearly with age (Y = 291.114447-3.01473X). The QCT-V of the 5th lumbar vertebra (L5) of normal cases also decreased linearly with age (Y = 309.641397-3.03986X), resembling that of L3. The ratio of the QCT-V of L5 to L3 (L5/L3, expressed as a percentage) definitely increased with age (Y = 86.5657441 + 0.58885064X). In radiated cases, the QCT-V of L3 in the non-radiated field did not change appreciably. The QCT-V of L5 in the radiated field was decreased from 20GY and reached 53.08 +/- 17.37% of the pre-radiation value after 50GY. The L5/L3 ratio was also decreased from 20GY and reached 55.47 +/- 15.32% of the pre-radiation value after 50GY. It becomes apparent that the QCT-V of the radiated lumbar vertebra is decreased during radiation. It is suggested that bone mineral metabolism may be disturbed in the early phase of radiation.

Bone Density↗
PubMed1991

Transport of cyclosporin A in kidney epithelial cell line (LLC-PK1).

The characteristics of cyclosporin A transport have been studied in cultured kidney epithelial cell line LLC-PK1. The uptake of cyclosporin A by LLC-PK1 cells was time-dependent and reached a steady state at about 30 min. The initial uptake was saturable and was inhibited by cyclosporin A analogs, cyclosporin C and D and by verapamil, but not by metabolic inhibitors such as 2,4-dinitrophenol and rotenone. Cyclosporin A uptake as well as efflux was strongly dependent on temperature. The Arrhenius plot for cyclosporin A uptake was biphasic, whereas the Arrhenius plot for sulfanilamide uptake, which is transported by a simple diffusion, was linear. These results indicate that a specific mechanism is concerned in the transport of cyclosporin A in LLC-PK1, cells.

Animals↗
PubMed1990

Moment analysis of drug disposition in kidney. III: Transport of p-aminohippurate and tetraethylammonium in the perfused kidney isolated from uranyl nitrate-induced acute renal failure rats.

A different manner of insufficiency of renal epithelial cell transport between the organic anion and cation, p-aminohippurate and tetraethylammonium, respectively, was observed in the perfused kidney isolated from uranyl nitrate-induced acute renal failure (ARF) rats. The single-pass outflow pattern of the perfused kidney was analyzed by noncompartmental moment analysis. The active tubular secretion was impaired faster than the reduction of glomerular filtration, and the tetraethylammonium secretion decreased at an earlier stage of ARF than p-aminohippurate. The apparent uptake rate constant from blood to cells of p-aminohippurate was reduced with the progress of ARF and associated with the amount of this drug secreted, whereas the uptake rate constant of tetraethylammonium did not change until the late stage of ARF. The mean residence time in renal epithelial cells of tetraethylammonium was prolonged with reduction of the amount to be secreted, while that of p-aminohippurate remained unchanged. Therefore, the uptake of p-aminohippurate across the basolateral membranes decreased gradually, and the transport across the brush border membranes was still unchanged after uranyl nitrate treatment. On the other hand, the secretion of tetraethylammonium from cells to lumen was impaired at first, and then the uptake from blood to cells was impaired. These results suggest that impairment by uranyl nitrate-induced ARF appears at the carrier-mediated transport process of the epithelial cell membranes for both organic anions and cations.

Acute Kidney Injury↗
PubMed1990

Moment analysis of drug disposition in kidney. II: Urine pH-dependent tubular secretion of tetraethylammonium in the isolated perfused rat kidney.

Effects of urine pH on the renal tubular secretion of an organic cation (tetraethylammonium, TEA) and an organic anion (p-aminohippurate, PAH) were investigated using the isolated erythrocyte-perfused rat kidney. The method was based on a multiple indicator dilution experiment and noncompartmental moment analysis. Treatment with sodium bicarbonate and sodium dihydrogen phosphate increased and decreased urine pH, respectively, but affected neither the condition of the perfused kidney nor the renal handling of albumin and inulin. In TEA studies, the increase of urine pH prolonged the mean residence time in renal epithelial cells (T cell) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vd drug). The decrease of urine pH did not affect these kinetic parameters. By contrast, PAH secretion was constant against the change of urine pH. Since any change in the basolateral membrane transport is reflected in Vd drug, the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T cell of TEA with the increased urine pH suggested a slow transport from cells to lumen across the brush-border membranes. The present results coincide with the hypothetical mechanism that organic cations are secreted via an active transport system, coupled to the countertransport of H+ into cells. In conclusion, the present method is useful to separately evaluate the transmembrane transport across both sides of the renal epithelial cells in a morphologically intact kidney.

Animals↗
PubMed1990

Characterization of epidermal growth factor receptors on plasma membranes isolated from rat gastric mucosa.

The binding of human epidermal growth factor (hEGF), beta-urogastrone, to plasma membranes isolated from rat gastric mucosa was studied to characterize gastric EGF receptors. The binding of [125I]hEGF was temperature dependent, reversible, and saturable. A single class of binding sites for EGF with a dissociation constant of 0.42 nM and maximal binding capacity of 42 fmol/mg protein was suggested. There was little change in the binding of [125I]hEGF upon addition of peptide hormones (secretin, insulin), antiulcer drugs (cimetidine), or an ulcer-inducing reagent (aspirin). Cross-linking of [125I]hEGF to gastric plasma membranes with the use of disuccinimidyl suberate resulted in the labeling of a protein of 150 kDa. These results indicate the presence of EGF receptors on plasma membranes of rat gastric mucosa.

Animals↗
PubMed1990

Contribution of monoamine oxidase(MAO) to the binding of tertiary basic drugs in isolated perfused rat lung.

The effect of tertiary basic drugs on mitochondrial MAO activity and the effect of MAO inhibitors (MAOIs) on basic drug accumulation in the isolated perfused rat lung were studied to clarify the role of MAO in drug binding to lung tissue. In the perfused lung preparation, the inhibition of MAO by basic drugs correlated well with their lipid solubilities and followed competitive kinetics. The inhibitory rank order (imipramine not equal to diphenhydramine greater than quinine greater than metoclopramide greater than procainamide) also correlated with their accumulation in the perfused lung. Moreover, MAOI treatment decreased the accumulation of basic drugs in the lung, and the potency of MAOIs to inhibit drug accumulation in the lung correlated with their MAO inhibitory activity. These results indicate that lung MAO has specific binding sites for basic drugs and may function as a drug reservoir.

Animals↗
PubMed1990

Alteration of propranolol pharmacokinetics and pharmacodynamics by quinidine in man.

The effects of quinidine on pharmacokinetics and pharmacodynamics of propranolol were investigated in a double-blind, placebo-controlled design. Healthy subjects of group A (n = 5) and group B (n = 11) were given oral propranolol (dose: group A 10 mg, group B 20 mg) with placebo or propranolol with quinidine (dose: group A 100 mg, group B 200 mg) on separate occasions. Quinidine induced a significant rise in the plasma concentrations of propranolol, and the area under the propranolol concentration-time curves (AUC) was also increased about 3-fold in both groups, indicative of an alteration of propranolol pharmacokinetics. In order to estimate the pharmacodynamic action of the pharmacokinetic interaction, the change in the heart rate during treadmill exercise testing was studied in group A. A significant inhibition of exercise-induced tachycardia was observed after administration of propranolol alone, but in combination with quinidine an even greater suppression was evident. These results indicate that the coadministration of propranolol and quinidine provides not only the potentiation of quinidine action by propranolol, which has been reported, but also the enhancement of propranolol action by quinidine, due to an increased plasma concentration of propranolol.

Adult↗
PubMed1990

Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells.

Pharmacokinetics of recombinant tissue-type plasminogen activator (rt-PA) produced in mouse C127 cells (t-PA(C127] and Chinese hamster ovary cells (t-PA(CHO] was investigated in chimpanzees. rt-PA was administered via a constant rate i.v. infusion for 60 min, and t-PA concentration and activity in plasma were measured during and after infusion. The noncompartmental parameters were calculated according to the moment analysis method, and a population pharmacokinetic analysis was performed to obtain the mean and interindividual variability of the pharmacokinetic parameters. The mean residence time of t-PA(C127) was significantly longer and the total body clearance was significantly less than that of t-PA(CHO). t-PA(C127) has an alpha-galactosyl moiety in its carbohydrate chains, whereas such a structure is not found in t-PA(CHO). These results demonstrate that two preparations of rt-PA's with different carbohydrate structures show different pharmacokinetics, and suggest that the carbohydrate structure can affect the efficiency of hepatic uptake of t-PA. A possible mechanism is an interaction of t-PA(C127) with the natural anti-alpha-galactosyl antibody. The anti-alpha-galactosyl antibody level in plasma decreased in association with the plasma levels of t-PA(C127) but was unaffected by t-PA(CHO) levels.

Animals↗
PubMed1990

Interaction of ofloxacin with organic cation transport system in rat renal brush-border membranes.

Ofloxacin, a pyridonecarboxylic acid derivative, was examined for its effects on the transport of tetraethylammonium (cation), cephalexin and cephradine (zwitterions), p-aminohippurate (anion) and D-glucose in brush-border membrane vesicles isolated from rat renal cortex. The initial uptake of tetraethylammonium in the presence or absence of an outward H+ gradient was inhibited by ofloxacin in a dose-dependent manner, although the equilibrium value of tetraethylammonium uptake was not affected. This inhibition occurred in a competitive manner (Ki = 0.11 mM). Ofloxacin also inhibited the initial uptake of cephalexin and cephradine, which can be transported via the H+/organic cation antiport system in renal brush-border membranes. In contrast, ofloxacin had no effect on p-aminohippurate. These data suggest that ofloxacin interacts with the organic cation transport system in renal brush-border membranes, and this system may play an important role in the tubular secretion of ofloxacin.

Animals↗
PubMed1990

Transport mechanisms of bestatin in rabbit intestinal brush-border membranes: role of H+/dipeptide cotransport system.

Bestatin [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine], a potent inhibitor of aminopeptidase B and leucine aminopeptidase, enhances the immune response to activate the defense mechanism of the living organism and suppresses the growth and metastasis of cancer. Bestatin has been effectively used by p.o. administration, but the mechanisms of intestinal absorption remain to be solved. The present study was undertaken to examine whether bestatin, a dipeptide containing an unusual amino acid, is transported via dipeptide carriers in intestinal brush-border membranes, by using cephradine as a probe for the H+/dipeptide cotransport system. The initial uptake of cephradine in the presence or absence of an inward H+ gradient, driving force, was inhibited by bestatin and this inhibition occurred in a competitive manner (Ki = 0.47 mM). The uptake of cephradine was stimulated by the countertransport effect of bestatin, the definitive criterion for ascertaining a common transport system. These findings indicate that bestatin, as well as cephradine and other p.o. cephalosporins, can be transported via dipeptide carriers in intestinal brush-border membranes.

Adjuvants, Immunologic↗