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M Hanano

Publications and source records attributed to M Hanano.

At least 199 records · Page 11Linked to original sources
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

Effects of organic anions on the uptake of 1-anilino-8-naphthalenesulfonate by isolated liver cells.

Uptake of the fluorescent probe, 1-anilino-8-naphthalene-sulfonate (I) into isolated rat liver cells was studied using both fluorescence and filtration methods. The time course of the fluorescence enhancement of I after addition to the isolated liver cells was analyzed in terms of rapid, medium, and slow phases. The slow phase (half-time approximately 7 min) was characteristic of viable cells. The fluorescence enhancement was proportional to the amount of I taken into the cells, as measured by the filtration method. The uptake of I followed Michaelis-Menten kinetics with an apparent Km of 39 microM and Vmax of 1.4 nmole/10(6) cells/min. The temperature coefficient (Q10) of the uptake of I was found to be approximately 1.9. No pH optimum was observed, and various metabolic inhibitors did not affect the uptake of I. Among the amino acid reagents used, only 2,4-dinitrofluorobenzene decreased the uptake of I (by approximately 45%). The effects of various organic anions on the uptake of I were measured. The inhibition of the uptake of I by sulfobromophthalein could be analyzed in terms of competitive inhibition; the slight inhibition by sodium taurocholate could not. It is concluded that the uptake of I is a carrier-mediated facilitated process, and that the carrier is common to both I and sulfobromophthalein.

Amino Acids↗
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

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↗
PubMed1983

Intestinal absorption of dl-alpha-tocopherol from bile salts and polysorbate 80 micellar solutions in rat.

The intestinal absorption of dl-alpha-tocopherol (VE) from various micellar solutions was studied by the in situ recirculating perfusion in rat small intestine. The perfused micellar solutions of VE were formed by sodium taurocholate (STC), sodium taurodeoxycholate (STDC) or polysorbate 80 (PS-80). The absorption ratio of VE was STC greater than STDC greater than PS-80 micellar solutions. The addition of egg lecithin (PC) to all micellar solutions caused the decrease of the absorption. The absorption ratio did not necessarily have a simple correlation with the VE solubilization in these micellar solutions. And it was also found that the absorption ratio correlated with the micellar size and with net water flux in the intestinal lumen.

Animals↗
PubMed1983

[Indium-111-oxine labeled platelet scintigraphy for detection of intracardiac and intravascular thrombi].

This study was designed to evaluate the efficacy of scintigraphy by using 111In-oxine labeled platelets for the detection of either intracardiac or intravascular thrombi. Fourteen cases of thrombi diagnosed or suspected on the basis of either angiography or two-dimensional echography were examined. They included four cases of left ventricular thrombi, three of left atrial thrombi, four of vascular thrombi and three of inflammatory disease. Platelet samples from the patients were labeled by 111In-oxine according to the method originated by Yui et al. The labeling efficiency was 72.4 +/- 9.8%. The platelets retained good function except for collagen aggregability. Hot areas of high quality in the scintigram were demonstrated in six cases including two with left ventricular thrombi, two with left atrial thrombi and two with vascular thrombi. These areas accorded well with the findings of angiography, echography or surgery. The removed thrombi had a layer of aggregated platelets on the surface. Platelet survival was shortened in a case of prosthetic valve endocarditis without a hot area, and was normal in four out of five cases including two with a hot area. It is concluded that this method is potentially predictive in detecting thrombi.

Adult↗
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↗
PubMed1982

Comparative physiologically based pharmacokinetics of hexobarbital, phenobarbital and thiopental in the rat.

A physiologically based pharmacokinetic model, which is an extension of the Bischoff-Dedrick multiorgan model, was developed to described the kinetics of barbiturates (hexobarbital, phenobarbital, and thiopental) in the rat. The model is composed of 11 organ or tissue compartments. The brain compartment was featured as a nonflow-limited organ for some low lipid soluble barbiturates. Michaelis-Menten constants for drug metabolism (Km, Vmax) were determined from in vitro experiments using liver microsomes. Binding of drugs to plasma and tissue proteins was measured in vitro using an equilibrium dialysis method. Distribution of drugs to red blood cells was measured in vitro with thiopental exhibiting a concentration dependent distribution. Penetration rates of the barbiturates into the brain were predicted on the basis of their lipid solubilities. A set of mass balance equations included terms for the inflow and outflow of drug carried by the perfusing blood, drug metabolism, protein binding, and penetration rate into the brain as well as blood flow rate and tissue mass. Solution of the system of equations yielded the time courses of drugs in each organ. However, predicted time course of drugs in plasma and brain were not in good agreement with those observed. Therefore, the tissue to plasma distribution ratios evaluated from in vivo experiments were substituted for the in vitro values, resulting in fairly good agreement between predicted and observed values.

Animals↗
PubMed1982

Physiologically based pharmacokinetics of drug-drug interaction: a study of tolbutamide-sulfonamide interaction in rats.

A blood flow rate-limited pharmacokinetic model was developed to study the effect of sulfonamide on the plasma elimination and tissue distribution of 14C-tolbutamide (TB) in rats. The sulfonamides (SA) used were sulfaphenazole (SP), sulfadimethoxine (SDM), and sulfamethoxazole (SMZ). The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e., lung, liver, heart, kidney, spleen, G.I. tract, pancreas, brain, muscle, adipose tissue, and skin, increased in the presence of SA, but except for brain, liver, and spleen, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did not show a significant alteration. This suggested that the tissue binding of TB is not affected by SA and that the increase of Kp is due mainly to the displacement of plasma protein-bound TB by SA. The concentrations of TB in several tissues and plasma were predicted by a physiologically based pharmacokinetic model using in vitro plasma binding and metabolic parameters, the plasma-to-blood concentration ratio and the tissue-to-plasma unbound concentration ratios having been determined from both the tissue and plasma concentrations of TB at the beta-phase after intravenous administration of TB and the plasma free fraction. The predicted concentration curves of TB in each tissue and in plasma showed good agreement with the observed values except for the brain, for which the predicted concentrations were lower than the observed values in the early time period. In the SP- and SDM-treated rats, the predicted free concentration of TB in the target organ, the pancreas, at 6 h was six times higher than that of the control rats. From these findings, it is suggested that physiologically based pharmacokinetic analysis could be generally useful to predict approximate plasma and tissue concentrations of a drug in the presence of drug-drug interaction.

Animals↗