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S Awazu

Publications and source records attributed to S Awazu.

At least 145 records · Page 8Linked to original sources
PubMed1983

Elimination kinetics of cefotaxime and desacetyl cefotaxime in patients with renal insufficiency and during hemodialysis.

The pharmacokinetics of cefotaxime, a new semi-synthetic cephalosporin for injection, was studied in 30 subjects with various degrees of renal function after a single 1-gram intramuscular injection. Serum and urinary concentrations of cefotaxime and desacetyl cefotaxime were determined by high pressure liquid chromatography. The pharmacokinetic parameters of cefotaxime were obtained using a one-compartment open model. The mean serum half-life of the parent compound (cefotaxime), 0.87 h in normal subjects, was prolonged to 2.35 h in hemodialysis patients. There was a significant linear correlation between the elimination rate constant of cefotaxime and creatinine clearance. The mean cumulative urinary recovery of the administered dose in the 24-hour urine was 51.7% as cefotaxime and 25.6% as desacetyl cefotaxime in normal subjects.

Adult↗
PubMed1983

p-Nitrophenol sulfation in rat liver cytosol: multiple forms and substrate inhibition of aryl sulfotransferase.

The p-nitrophenol (PNP) sulfate conjugation rate in rat liver cytosol at pH 7.4 under 10-30 microM 3'-phosphoadenosine-5'-phosphosulfate (PAPS) was decreased at 10-200 microM PNP and increased again at more than 200 microM PNP. The higher the PAPS concentration, the more remarkable such substrate inhibition. These results indicate that the substrate inhibition was due to the direct interaction of PNP with the aryl sulfotransferase (phenol sulfotransferase, PST). The PST reaction was thermolabile at less than 20 microM PNP but thermostable at more than 200 microM PNP. The Km values for PAPS obtained in the PST reactions where the inhibition was not observed was about 23 microM at 2.5-5 microM PNP and 11-14 microM at more than 200 microM PNP. And the Km values for PNP at more than 500 microM PNP was 2.2-2.6 mM. On the other hand, the inhibition in the PST reaction at pH 5.6 was observed at much higher PNP concentration, approximately 200 microM, than that at pH 7.4. Based on these characteristic results, the correspondence of the PST catalyzing the PNP sulfate conjugation (pH 7.4) at the low and high concentrations of PNP in the liver cytosol with the multiplicity obtained in the purified preparation of the liver previously reported by another researchers was compared and discussed. Finally the selection of an endogeneous substrate for estimating such complexed sulfate conjugation in advance in each individual man was also proposed.

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↗
PubMed1982

Pharmacokinetic evidence for the occurrence of extrahepatic conjugative metabolism of p-nitrophenol in rats.

p-Nitrophenol (PNP), as a model compound for the study of conjugative metabolism, was administered intravenously to rats. PNP and its conjugated metabolites, i.e. PNP-glucuronide (PNP-Glu) and PNP-sulfate (PNP-Sul), were determined in body fluids by reversed-phase high-performance liquid chromatography using ion-pair systems. Linear pharmacokinetics was applicable in the dose range of 1.6 to 8 mg/kg. The metabolic clearance which was obtained from the area under the PNP blood concentration curve (AUCiv) and from the excretion ratio of the total conjugates as PNP-Glu and PNP-Sul was so close to the hepatic blood flow that the PNP conjugation reactions seemed to be limited by the hepatic blood flow, that is the hepatic extraction ratio (EH) was expected to be 1. However, AUCpv, following portal vein administration of PNP (4 mg/kg), was not zero but was significantly different from AUCiv after the same dosing (P less than 0.05). Consequently, comparison between the AUC values from both dosing routes and the excretion ratio of PNP-Glu and PNP-Sul gave and EH of 0.43. Such a difference in EH obtained by the two methods suggested a contribution by extrahepatic conjugative metabolism. It was shown that the intrinsic hepatic clearance obtained, assuming exclusively hepatic conjugative metabolism, was certainly overestimated. Furthermore, the results of the conjugation reaction in tissue homogenates suggested a contribution by extrahepatic glucuronidation.

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

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

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

Correlation of drug conjugative metabolism rates between in vivo and in vitro: glucuronidation and sulfation of p-nitrophenol as a model compound in rat.

The correspondence of conjugative metabolism rates in vivo and in vitro was studied in rat using p-nitrophenol (PNP) as a model compound. In PNP-glucuronide conjugation, the hepatic intrinsic clearance calculated from Km and Vmax obtained in the isolated liver cells was approximately three times larger than that calculated by the in vivo blood concentration on the basis of the linear pharmacokinetic concepts, but this difference was not considered essential. On the other hand, in PNP-sulfate conjugation, some inhibition in the isolated liver cells, which was not expected in the in vivo blood concentration, was found at more than 5 microM PNP. Such inhibition mechanism could not be elucidated by the inorganic sulfate concentration in the reaction medium. Accordingly, it was suggested that some unknown reaction mechanism still remained to be studied for the applicability of the conjugation rates in the isolated liver cells, especially sulfation rates, to the pharmacokinetic study in vivo.

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

Pharmacokinetics of cefroxadine in healthy volunteers and patients with impaired renal function.

The pharmacokinetics of cefroxadine, a new orally active broad-spectrum cephalosporin, was studied in healthy volunteers and patients with impaired renal function after a single oral dose of 500 mg. The pharmacokinetic parameters of cefroxadine were obtained by analysing the serum level data of the drug based on a one-compartment open model. The mean serum half-life of cefroxadine was 0.97 h in healthy subjects, and was prolonged to 41.7 h in patients with a creatinine clearance of less than 5 ml/min. There was a significant linear correlation (p less than 0.001) between the elimination rate constant of the drug and the creatinine clearance. In healthy subjects, 71% of the administered dose was excreted in the urine collected over the first 6 h.

Adult↗
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↗