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M Hanano

Publications and source records attributed to M Hanano.

At least 217 records · Page 12Linked to original sources
PubMed1982

In vitro and in vivo evaluation of the tissue-to-blood partition coefficient for physiological pharmacokinetic models.

An important parameter used in physiologically based pharmacokinetic models is the partition coefficient (Kp), which is defined as the ratio of tissue drug concentration to the concentration of drug in the emergent venous blood of the tissue. Since Kp is governed by reversible binding to protein and other constituents in blood and tissue, an attempt was made here to estimate the Kp values for a model drug ethoxybenzamide (EB) by means of in vitro binding studies and to compare these Kp values to those obtained from in vivo kinetic parameters observed following the administration of EB by two different routes, i.e., i.v. bolus injection and constant rate infusion. The Kp values obtained by using these three different methods were in reasonably good agreement suggesting that binding data obtained in vitro can successfully be used to estimate in vivo distribution.

Animals↗
PubMed1982

Physiological pharmacokinetics of ethoxybenzamide based on biochemical data obtained in vitro as well as on physiological data.

Ethoxybenzamide (EB) concentrations in plasma and various tissues were simulated using a physiological pharmacokinetic model. The biochemical parameters, such as plasma and tissue binding constants and Michaelis-Menten constants for EB deethylation, which were needed for these simulations, were, however, obtained from in vitro data. The simulations predicted well the observed data in plasma and various tissues of the rat. Furthermore, animal scale-up predicted reasonably well the concentrations of EB in plasma and various tissues of the rabbit from data gathered in rats.

Animals↗
PubMed1982

Solvent drag effect in drug intestinal absorption. I. Studies on drug and D2O absorption clearances.

It was shown that the intestinal absorption clearance of D2O (CLD2O) could be a more appropriate index to study the solvent drag effect than water volume flow which was the difference between water influx and outflux in the intestinal lumen. Then, the correlation between the intestinal absorption clearances of drugs (CLdrug) and CLD2O were studied using the in situ recirculating method in the rat small intestine. The drugs used were low molecular drugs, that is, benzoic acid, salicylic acid, p-hydroxybenzoic acid and antipyrine, and comparably high molecular drugs, that is, cephalexin (CEX), cefroxadine (CXD) and cephalothin (CET). CLdrug and CLD2O were obtained in hypertonic, isotonic and hypotonic perfused solution adjusted with sodium chloride. Consequently, the correlations for all drugs except CET were significant and high solvent drag effects were observed. CLdrug of benzoic acid, salicylic acid and antipyrine were approximately equal to CLD2O, suggesting that the intestinal mucosa could not distinguish these lower molecular drugs from water. For the high molecular drugs such as cephalosporins, however, some extent of reflection from the membrane was certainly found in CEX and CXD, and the extent in CET was assumed much larger than CEX and CXD, resulting that the contribution of solvent drag in CET could not be found. Consequently, it was suggested that the solvent drag had some important role in the intestinal absorption of cephalosporins.

Animals↗
PubMed1982

A drug absorption model of the intestinal tract based on the two-dimensional laminar flow in a circular tube.

A drug absorption model was developed by using the two-dimensional laminar flow in a circular tube, considering a small water absorption or secretion in the intestinal perfusion experiment. The concentration in the intestinal tract was determined 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 not only from the inlet to the outlet but also from the center of the intestinal tract to the intestinal wall. The concentration at the aqueous-intestinal membrane interface was changed by the radial component of velocity, so it was suggested that the effective thickness of the aqueous diffusion layer (unstirred water layer) varies with a small water absorption or secretion.

Cell Membrane Permeability↗
PubMed1982

Prediction of renal tubular secretion of tetraethylammonium bromide by use of endogenous N1-methylnicotinamide in the rat.

The renal secretion of an endogenous N1-methylnicotinamide (NMN) and its use-fullness as an index of the renal secretion clearance of tetraethylammonium bromide (TEA), a representative organic cationic drug, was examined in the rats treated with folic acid, glycerol and uranyl nitrate, respectively. There was a statistically significant correlation between the renal secretion clearance of TEA and that of NMN in the intact and acute renal failure rats (r = 0.969, p less than 0.001). It was suggested that the renal secretion clearance of the endogenous NMN could be used as an index to assess the renal tubular function for the secretion of organic cationic drugs like TEA.

Animals↗
PubMed1982

Solvent drag effect in drug intestinal absorption. II. Studies on drug absorption clearance and water influx.

In order to study the solvent drag effect, it was shown that back flux of absorbed drug from blood to intestinal lumen can be ignored but the back flux of water cannot. Then, apparent water influx was calculated as a new measure of solvent drag based on the model in which the back flux of D2O from blood to lumen was considered during absorption. Consequently, the correlation between drug absorption clearance (CLdrug) and apparent water influx was highly significant for benzoic acid, salicylic acid, p-hydroxybenzoic acid, antipyrine, cephalexin (CEX) and cefroxadine (CXD), resulting the high solvent drag effects were detected. The mean values of the slopes in the regression lines of CLdrug versus apparent water influx, i.e., sieving coefficients, were smaller than one for benzoic acid and salicylic acid, but the values were not significantly different from one. The sieving coefficients of the other drugs were significantly smaller than one. From these results, the molecular size dependence in the reflection from the intestinal membrane during absorption was clearly shown. And the intercepts of the regression lines including diffusive permeabilities were found to be significantly different from zero in CEX and CXD. On the basis of the sieving coefficients and intercept values obtained in such ways, the appropriateness of this model was discussed.

Animals↗
PubMed1982

1-Anilino-8-naphthalene sulfonate binding site on human erythrocyte membrane using fluorescence lifetime and polarization.

It was shown that the human erythrocyte ghost membrane had two kinds of binding site for 1-anilino-8-naphthalene sulfonate (ANS) from binding kinetics. In measuring the fluorescence lifetime of ANS in the human erythrocyte ghost membrane suspension, two kinds of fluorescence lifetime were obtained: tau 1 = 15 ns at low ANS concentration and tau 2 = 8.4 ns at high ANS concentration. Comparing the results obtained from binding kinetics with those from fluorescence lifetime, it was considered that more hydrophobic binding site with fluorescence lifetime tau 1 contained the binding site with high and low binding constant and less hydrophobic binding site with fluorescence lifetime tau 2 corresponded to the binding site with low binding constant. From the results of binding kinetics of ANS to the erythrocyte membrane and the extracted membrane components (proteins and lipids), and those of the rotational relaxation time obtained from the ANS polarization in the erythrocyte membrane suspension, it was shown that the binding sites of ANS in the human erythrocyte ghost membrane were mainly composed of proteins at low ANS concentrations and lipids at high ANS concentrations.

Anilino Naphthalenesulfonates↗
PubMed1982

[Therapeutic results of DCMP therapy (2M-80) in acute non-lymphocytic leukemia--the relationship between the residual leukemic cells and duration of remission].

In this study the duration of complete remission by daunomycin, cytosine arabinoside (Ara-C), 6MP and prednisolone (DCMP) therapy using a large dose of Ara-C (200 mg) (protocol 2M-80) was compared with that of DCMP therapy with a low dose of Ara-C (80-160 mg) in acute non-lymphocytic leukemia (ANLL). In protocol 2M-80, the chemotherapy was continued until leukemic blasts in marrow were attained below 3%. Complete remission was induced in about 80% of ANLL patients in both chemotherapies. However, the duration of remission in protocol 2M-80 appeared to be much longer than that of DCMP therapy with a low, dose of Ara-C. This difference was dependent not on the consolidation and maintenance therapy, but on the total dose of Ara-C used and leukemic blasts left in marrow at the end of chemotherapy. This suggests that it is important to reduce leukemic blasts in marrow as low as possible by induction chemotherapy to obtain a long-term remission in ANLL.

Acute Disease↗
PubMed1982

[Infections during induction chemotherapy of acute leukemia and their control V. Clinical evaluation of a large dose of amikacin injected intravenously].

In this study, we treated severe infections (21 cases) accompanied with induction chemotherapy in 20 patients with acute leukemia by the combination of a large dose (600 approximately 1,200 mg/day) of amikacin with other antibiotics. Infections during induction chemotherapy of acute leukemia consisted of sepsis (8 cases), pneumonia (7) and others (6), and most of causative organisms were Gram-negative bacteria, such as Ps. aeruginosa (7 strains), Flavobacterium (5), Serratia (3), Ps. cepacia (2), E. coli (2) and others. The combination chemotherapy of a large dose of amikacin with other antibiotics was found to be effective (71.4%) for such infections. Side effects were negligible except for drug eruption. Therefore, a large dose of amikacin should be given for the treatment of severe infections accompanied with induction chemotherapy of acute leukemia.

Adolescent↗
PubMed1981

Effect of sulfadimethoxine on thiopental distribution and elimination in rats.

The effect of sulfadimethoxine on the distribution and elimination of thiopental was examined by comparing the change in the steady-state volume of distribution (Vss) determined from both in vivo plasma elimination and in vitro serum and tissue binding studies in rats. The plasma disappearance of thiopental after a 12-mg/kg iv dose followed a biexponential decline in both the control and sulfadimethoxine-treated rats. The plasma thiopental concentrations under the steady-state plasma sulfadimethoxine concentration (500 micrograms/ml) were significantly lower than those of the control rats. In the sulfadimethoxine-treated rats, the pharmacokinetic parameter beta significantly decreased while Vss significantly increased to 3.6-fold that of the control rats. With sulfadimethoxine, a significant increase was observed in the apparent dissociation constant (Kd) of thiopental to serum protein by equilibrium dialysis, but the total number of binding sites was not altered. The in vitro serum free fraction of thiopental was increased to about 2.6-fold in the presence of sulfadimethoxine. The free fraction of thiopental in the main distribution tissues (liver, muscle, and adipose) was determined by equilibrium dialysis with and without sulfadimethoxine. No significant changes were observed in the presence of sulfadimethoxine. The calculated Vss, determined by the free fractions from in vitro binding experiments, also showed a significant increase. The ratio of Vss with sulfadimethoxine to that of the control rats was 2.8. The total clearance did not change, but the intrinsic clearance decreased to one-half of that of the control rats due to the increase of the serum free fraction by sulfadimethoxine. It was concluded that sulfadimethoxine caused a displacement of thiopental in plasma protein binding, which significantly increased the free fraction of thiopental, and this result may explain the significant increase of Vss and the decrease of both beta and intrinsic clearance. Tissue binding of thiopental, however, was unaffected by sulfadimethoxine.

Animals↗
PubMed1981

Interspecies difference in drug protein binding-temperature and protein concentration dependency: effect on calculation of effective protein fraction.

The effects of temperature and protein concentration on the binding of thiopental to bovine and rat serum albumin and to rat plasma were examined using flow and equilibrium dialysis techniques. The effects of temperature and protein concentration were peculiar to each species. The binding of thiopental to rat serum albumin or rat plasma was sensitive to temperatures between 4 and 37 degrees, whereas the binding to bovine serum albumin was sensitive to a protein concentration difference of 0.1-4.44%. Therefore, the effective protein fraction is affected by various sets of binding parameters of albumins determined under various temperatures and protein concentrations. Thus, a semi-predictive method for plasma or tissue binding may be unsuccessful unless proper binding parameters are used.

Animals↗
PubMed1981

The correlation between drug binding to the human erythrocyte and its hemolytic activity.

Cationic phenothiazine derivatives, anionic anthranilic acid derivatives and fluorescent probe 1-anilino-8-naphthalene sulfonate (ANS) which had hemolytic activities were used to investigate hemolysis of human erythrocyte. The observed hemolytic activities of drugs could divided into two categories: (1) the difference of the binding activity of drugs to the erythrocyte and (2) the difference of the membrane perturbation activity of drugs bound to the erythrocyte. The human erythrocyte had two kinds of binding sites for any drug used. The first site of them was already saturated before hemolysis occurred and the second site of them may play an important role in hemolysis by these drugs.

Anilino Naphthalenesulfonates↗
PubMed1981

Comparative hepatic transport of sulfobromophthalein and its glutathione conjugate in rats.

The hepatic transport of sulfobromophthalein (BSP) and its glutathione conjugate (BSP-GSH) were compared in rats by pharmacokinetic analysis in an attempt to determine the effect of conjugation on the over-all transfer of BSP from blood into bile. In the control rats, the plasma disappearance of BSP was faster than that of BSP-GSH, while the biliary excretion rate of BSP-GSH was significantly higher than that of BSP for the first 10 min. No significant difference in the total amount excreted in the bile for 4 hr was observed between two dyes. In the rats chronically intoxicated with carbon tetrachloride, typical delays were shown in both the plasma disappearance and the biliary excretion of BSP-GSH. In the control rats, the pharmacokinetic parameters, k12 and k23 of BSP-GSH were significantly smaller than those of BSP, while k34 was significantly greater than those of BSP. In the intoxicated rats, significant decreases were observed in k12, k23 and k34. The binding of BSP and BSP-GSH to the Y-fraction prepared from the control and intoxicated rats were studied by equilibrium dialysis. In the control rats, the number of high affinity bindings sites (n1) of BSP-GSH was significantly smaller than that of BSP, while no significant difference was revealed in the binding constant of the high affinity binding site (K1). In the intoxicated rats, both n1 and K1 of BSP-GSH were significantly smaller than those of the control rats. It was suggested that the glutathione conjugation might not play as the rate-determining step in the over-all hepatic transport of BSP.

Animals↗
PubMed1981

The study on the biological fate of paraben at the dose of practical usage in rat. III. The effects of salicylic acid on the fate of ethyl paraben.

The biological fates of ethyl paraben were investigated after the simultaneous administration with salicylic acid. Those fates were compared with those of ethyl paraben alone obtained in the previous experiments. The biological fates of ethyl paraben after the simultaneous administration with salicylic acid were different from those of ethyl paraben alone as reported in the previous reports. The excretion of unconjugated p-hydroxybenzoic acid, which is a hydrolyzed product of ethyl paraben, increased and those of p-hydroxyhippuric acid, glycine conjugate of p-hydroxybenzoic acid, and p-hydroxybenzoyl glucuronide, its ester type glucuronide, decreased. The blood concentration patterns were considerably different from those of ethyl paraben alone, especially the elimination of every metabolite was delayed. Pharmacokinetic analyses on the data of blood concentration were carried out and the results also show the interaction of salicylic acid on the biological fate of ethyl paraben.

Animals↗