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Biomedical subjects

T Iga

Publications and source records attributed to T Iga.

At least 271 records · Page 15Linked to original sources
PubMed1984

Estimation of renal secretory function for organic cations by endogenous N1-methylnicotinamide in rats with experimental renal failure.

To assess whether the secretory clearance of N1-methylnicotinamide (NMN), an endogenous organic cation, represents renal tubular secretion of the organic cation, the relationship between the secretory clearance of NMN, CLscn(NMN), and that of tetraethylammonium bromide (TEA), CLscn(TEA), was examined in normal and experimental renal failure (ERF) rats. TEA was selected as a representative organic cation secreted by the kidney. ERF was induced by glycerol, folate, salicylate, uranium, and gentamicin, substances which have been demonstrated to produce specific damage to the kidney by pathophysiological studies. Glomerular filtration rate (GFR), CLscn(NMN), and CLscn(TEA) decreased significantly in most of ERF rats, while blood urea nitrogen (BUN) increased significantly in all ERF rats. There was a statistically significant correlation (r = 0.952, p less than 0.001) between the endogenous CLscn(NMN) and CLscn(TEA) in both the normal and ERF rats. Correlation analysis revealed that CLscn(NMN) was superior to GFR in the degree of relationship to CLscn(TEA), but BUN could not be used as an index for the secretion of NMN or TEA. Although the plasma concentration of NMN in most of the ERF rats was much higher than that in the normal rats, it affected neither the urinary clearance of NMN itself nor the excretion of TEA. From these findings, we propose that CLscn(NMN) can be used as an index to assess renal tubular function for the secretion of organic cations that are excreted by both filtration and secretion without reabsorption.

Acute Kidney Injury↗
PubMed1984

Effect of late pregnancy on salicylate, diazepam, warfarin, and propranolol binding: use of fluorescent probes.

Serum protein binding was measured in six women 38 wk pregnant and in five control subjects. Three distinct binding sites for drugs on human serum albumin have been identified. To determine whether changes in binding during pregnancy occur for common drugs or only for drugs that bind to a specific binding site, serum protein binding of three drugs--diazepam (site I), warfarin (site III), and salicylate--and four fluorescent probes--dansylsarcosine (site I), 1-anilino-8-naphthalenesulfonate (site I), 7-anilinocoumarin-4-acetic acid (site II), and 5-dimethylaminonaphthalene-1-sulfonamide (DNSA) (site III)--were determined in control and pregnant sera. Unbound fractions of diazepam and salicylate in pregnant women increased but the unbound fraction of warfarin did not change. Dissociation constants (Kd1) of all fluorescent probes but DNSA were almost the same in control and pregnant sera, while the Kd1 of DNSA in pregnant serum was approximately 50% of control. Binding capacities of all probes decreased, which was attributed to decreased serum albumin concentration. We concluded that serum protein binding of drugs that bind to site I or site II on albumin decreased largely because of the reduced serum albumin concentration during pregnancy and that the binding of drugs that bind to site III changed little because of compensating effects of the decrease in serum albumin concentration and the increase in binding affinity to serum albumin. Serum concentration of alpha 1-acid glycoprotein and serum binding of propranolol did not change in pregnant women.

Adult↗
PubMed1984

Comparison between in-vivo and in-vitro tissue-to-plasma unbound concentration ratios (Kp,f) of quinidine in rats.

The comparison between in-vivo and in-vitro tissue-to-plasma concentration ratio of drug unbound (Kp,f) has been made using quinidine as a model for weak basic drugs. In-vitro Kp,f-values were calculated from the binding data to tissue homogenates determined by equilibrium dialysis. In-vivo Kp,f-values were calculated from the tissue distribution data after intravenous administration of quinidine, by considering the difference in the unbound concentration between plasma and the tissues produced by the pH difference across the cell membrane. It was concluded that the extensive tissue distribution of quinidine observed in-vivo may be explained by tissue binding and the pH-difference across the cell membrane in most tissues.

Animals↗
PubMed1984

Nuclear binding as a determinant of tissue distribution of adriamycin, daunomycin, adriamycinol, daunorubicinol and actinomycin D.

The tissue distribution mechanism of adriamycin (ADR), its relatives, daunomycin (DNR), adriamycinol (ADR-ol), daunorubicinol (DNR-ol) and actinomycin D (ACT-D) has been studied in rats and rabbits. The following evidences with respect to tissue distribution of ADR were obtained: 1) remarkable binding of ADR to tissue homogenate, 2) significant difference in the tissue binding of ADR among tissues, 3) exclusive localization of ADR in cell nucleus, 4) good correlation between the tissue binding of ADR and the tissue desoxyribonucleic acid (DNA) concentration, 5) comparatively good coincidence between the experimentally determined tissue binding of ADR and that calculated from in vitro nuclear binding parameters reported and the tissue DNA concentration, and 6) no correlation between the concentration of tissue phospholipids (i.e. cardiolipin, acidic phospholipids and total phospholipids) and the Kp value of ADR in rats. From these findings, it was confirmed that the nuclear binding is a determinant of the extensive tissue distribution of ADR and that a remarkable variation in the tissue concentration of ADR is due mainly to the difference in the tissue DNA concentration. Furthermore, good correlations were demonstrated between the DNA concentration and Kpapp values of DNR and ACT-D in rats and DNR, ADR-ol and DNR-ol in rabbits. Hence, it is suggested that there is a common mechanism of in vivo tissue distribution of ADR and its relatives which can intercalate to DNA and the determinant of characteristic tissue distribution is nuclear binding of these antibiotics.

Animals↗
PubMed1984

A laminar flow absorption model for a carrier-mediated transport in the intestinal tract.

A laminar flow absorption model for a carrier-mediated transport was developed to analyze the data of the intestinal single perfusion experiment. By using this model, we calculated the absorption rate and the concentration of the substance (drug) at the aqueous-intestinal membrane interface (cwall). The absorption rate was smaller than that predicted by the Michaelis Menten equation, using the concentration at the inlet (c0). The apparent Michaelis constant (Km,app) was larger than the true Michaelis constant (Km), if the data were analyzed by using the simulation curve of the absorption rate vs. c0 as the usual method. This is because cwall was smaller than c0. But the maximal transport velocity (Vmax) was little affected, because cwall became almost equal to c0 when c0 was high. By using this model, we can determine the values of Vmax and Km which are not biased by the unstirred water layer in the intestinal tract.

Biological Transport↗
PubMed1983

Concentration profile in the intestinal tract and drug absorption model: two-dimensional laminar flow in a circular porous tube.

The calculation method of the concentration profile in the intestinal tract was developed by adapting the two-dimensional laminar flow in a circular porous tube to the fluid flow and considering a small water absorption or secretion in the intestinal perfusion experiment. The concentration profile was changed by the axial component of velocity, the radial component of velocity, the membrane permeability coefficient, the reflection coefficient and so on. According to the calculated values, the concentration decreased from the center of the intestinal tract to the intestinal membrane as well as from the inlet to the outlet of the intestinal tract. The concentration at the aqueous-intestinal membrane interface increased when water was absorbed and decreased when water was secreted. Consequently, the drug absorption (or secretion), not only because of the effect of the solvent drag but also because of the increase (or decrease) of the concentration gradient at the aqueous-intestinal membrane interface. Using the proposed model in the present study, the concentration at the aqueous-intestinal membrane interface can be calculated directly under the various conditions. Therefore, the true membrane permeability coefficient can be obtained by a graphic method, without correcting the apparent membrane permeability coefficient by the effective thickness of the aqueous diffusion layer (the unstirred water layer).

Animals↗
PubMed1983

Effect of chlorpromazine on hepatic transport of indocyanine green in rats.

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V2 and total body clearance (CLtot) in CPZ 10 mg/kg treated rats and k34, V2 and CLtot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k21 in both CPZ-treated groups; V1 was not altered. The apparent liver-to-plasma concentration ratio (Kp,app) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.

Animals↗
PubMed1983

Melanophores of Zacco temmincki (Teleostei) are light sensitive.

The responses of melanophores of a cyprinid fish Zacco temmincki to changes in illumination were examined in isolated scale preparations of the adult fishes. Melanosomes in the melanophores aggregated in darkness and dispersed in light. These responses were invariably induced, even in denervated melanophores. These light responses, the dark-induced aggregation and the light-induced dispersion, were not affected by a number of alpha and beta adrenergic blocking agents. It was concluded that the melanophores of Zacco temmincki were themselves light sensitive and responded directly to light by melanosome translocations. The light responses were quantitatively assessed in relation to the intensity of illumination.

Animals↗
PubMed1983

Effect of quinidine on digoxin distribution and elimination in guinea pigs.

The effect of quinidine on the distribution and elimination of digoxin was examined by comparing the change in the steady-state volume of distribution (Vdss), determined both from in vivo plasma elimination and tissue distribution and in vitro serum binding studies, with that in the total body clearance (CLtot) determined from biliary, renal, and metabolic clearances in guinea pigs. The plasma disappearance of digoxin after a 250-micrograms/kg iv dose followed a triexponential decline in both the control and quinidine-treated guinea pigs. In the quinidine-treated guinea pigs, the pharmacokinetic parameters Vdss and CLtot significantly decreased to approximately half of that for the control guinea pigs. The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e. liver, heart, muscle, and brain, at 6 hr after bolus injection of digoxin decreased in the presence of quinidine. The serum free fraction and the plasma-to-blood concentration ratio of digoxin in the therapeutic range did not show a significant alteration in the presence of quinidine. This suggested that the decrease of Kp is due mainly to the inhibition of tissue distribution of digoxin by quinidine. The biliary clearance (CLB) and renal clearance (CLR) also significantly decreased in the presence of quinidine. It was concluded that quinidine caused a inhibition of digoxin in the tissue binding or uptake, which significantly decreased the Kp values of digoxin; this result may explain the significant decrease of Vdss. Moreover quinidine may be the cause of a reduction of biliary, renal, and metabolic clearances, which significantly decrease the CLtot of digoxin.

Animals↗
PubMed1983

Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model.

A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat, incorporating anatomical, physiological, and biochemical parameters, i.e., tissue volume, blood flow rate, serum free fraction, distribution of diazepam into red blood cells, drug metabolism and tissue-to-blood distribution ratio. The serum free fraction of diazepam was determined by equilibrium dialysis at 37 degrees C and was constant over a wide concentration range. Partition of diazepam between plasma and erythrocytes was determined in vitro at 37 degrees C, and the resultant blood-to-plasma concentration ratio was constant over a wide concentration range. The enzymatic parameters (Km, Vmax) of the eliminating organs, i.e., liver, kidney, and lung, previously determined using microsomes, were used for the prediction. The tissue-to-blood distribution ratios inferred by inspection of the data when pseudoequilibrium is reached after i.v. bolus injection of 1.2 mg/kg diazepam were corrected according to the method of Chen and Gross. Predicted diazepam concentration time-course profiles in plasma and various organs or tissues, using an 11-compartmental model, were compared with those observed. Prediction was successful in all compartments including brain, the target organ of diazepam. Scale-up of the disposition kinetics of diazepam from rat to man was also successful.

Animals↗
PubMed1983

Basic properties of beta adrenergic receptors mediating melanosome dispersion of melanophores in a cyprinid fish, Zacco temmincki.

In melanophores of a cyprinid fish, Zacco temmincki, receptor mechanisms of melanosome dispersion induced by catecholamines were examined. While possessing a melanosome-aggregating action in higher concentrations, isoproterenol and epinephrine in lower concentrations acted to disperse melanosomes. Norepinephrine, epinine and dopamine altered their action from melanosome aggregation to melanosome dispersion after alpha adrenergic blockade. The catecholamine-induced melanosome dispersion was inhibited by beta adrenergic blocking agents. Mediation of dispersion is regulated through beta adrenergic receptors. The beta adrenergic responses were unaffected by mersalyl, a sulfhydryl inhibitor. A prospective substance acting in dispersing melanosomes appears to be adrenaline, but not noradrenaline.

Animals↗
PubMed1983

Electric stimulation experiments on leucophores of a freshwater teleost, Oryzias latipes.

1. Electric stimulation experiments on the central nerve and on isolated scales of a freshwater teleost, Oryzias latipes, confirmed that the leucophores, like the melanophores, were controlled by the nerve. 2. AC stimulation induced pigment dispersion of the innervated leucophores. The response was not of the all or none type. 3. AC selectively acts on the nerve fibers to produce propagating excitation. 4. The transmitter released from the nerve terminals is suspected to be noradrenaline, and the postsynaptic receptor is of an adrenergic beta type.

Animals↗
PubMed1983

Effect of experimental acute renal failure on intrinsic renal tubular secretory clearance of organic cations in rats.

Effect of experimental acute renal failure (EARF) on the intrinsic renal tubular secretory clearance (CLscnint) of tetraethylammonium bromide (TEA) and N1-methylnicotinamide (NMN) was examined in rats treated with glycerol, folate, salicylate, uranium and gentamicin. The values of CLscnint was calculated by an equation incorporating the determinants of the renal clearance (CLr), i.e., renal tubular secretory clearance (CLscnr), glomerular filtration rate (GFR), renal plasma flow (RPF), free fraction of the drug in plasma (fp) and fraction (Freabs) of the drug reabsorbed after filtration and secretion in the urine. In the EARF-rats, the values of CLscnint of NMN and TEA were decreased by 0.017-0.575 times and by 0.005-0.737 times as compared to those of the normal rats, respectively. It was suggested that the decreases in CLscnr of both NMN and TEA were due not to the decrease in RPF, but to that in CLscnint.

Acute Kidney Injury↗
PubMed1983

Effect of chlorpromazine on intestinal absorption of sulfamethoxazole in rats.

The effect of chlorpromazine (CPZ) on the intestinal absorption of sulfamethoxazole (SMZ) was studied in isolated perfused rat small intestine by comparing two determinants, i.e. the epithelial permeability and the intestinal blood flow. The appearance rate of SMZ in blood in the presence of CPZ decreased to one-half of the control without CPZ. The pH of perfusion solution was significantly decreased by CPZ after 10 min perfusion. According to the Winne's absorption model, CPZ did not change the apparent epithelial permeability of SMZ, but decreased the epithelial permeability of unionized SMZ due to the decrease in the pH of perfusion solution by CPZ. It was also suggested that CPZ decreased the fraction of the total blood flow rate in the subepithelial capillaries to less than one-half.

Animals↗
PubMed1982

Effect of chlorpromazine on isolated rat hepatocytes.

The effect of chlorpromazine hydrochloride (CPZ) (1-500 microM) on plasma membrane permeability and mitochondrial respiratory function of isolated rat hepatocytes was studied. The endogenous oxygen consumption stimulated by 1 mM succinate was increased significantly by 5 microM CPZ, whereas the ability to exclude trypan blue (TB) was decreased significantly by 100 microM CPZ. The release of a cytosomal enzyme, lactate dehydrogenase (LDH), was increased significantly by 50 microM CPZ, whereas the release of glutamic-opalacetic transaminase (GOT) was increased significantly by 100 microM. The endogenous oxygen consumption was decreased significantly by 150 microM CPZ. The respiration control ratio by 2 microM carbonylcyanide-m-chlorphenyl hydrazon (CCP) showed significant decreases at all concentrations of CPZ studied; and this might be attributable to the suppression by CPZ of the respiratory stimulation induced by CCP. The results indicated that CPZ at a low concentration (5 microM) first produced a significant change in plasma membrane permeability to low molecular substances such as succinate and then at higher concentrations (50-100 microM) produced significant release of the cytosomal and mitochondrial enzymes, LDH and GOT. They also indicated that the concentrations of CPZ which produced significant effects on respiratory function were higher (above 150 microM) than those which produced significant changes in plasma membrane permeability of hepatocytes.

Animals↗