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Biomedical subjects

T Iga

Publications and source records attributed to T Iga.

At least 289 records · Page 16Linked to original sources
PubMed1982

Uptake of bile acids by isolated rat hepatocytes.

Hepatic uptake of five common bile acids was examined in isolated rat hepatocytes. Taurocholic acid (TCA), glycocholic acid (GCA), cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were studied. Uptake was extremely rapid and was linear for at least 45 sec for all bile acids tested at substrate concentrations from 1 to 400 micrometers. Both nonsaturable binding to the cell surface membrane and the initial rate of uptake (V0) of the dihydroxy bile acids (DCA and CDCA) were about ten times greater than those of the trihydroxy bile acids (TCA, GCA and CA) which correlates with the higher lipophilicity of the dihydroxy bile acids. Kinetic analysis demonstrated that uptake of these bile acids was due both to a saturable process and a linear process. The apparent diffusion constant (Dapp) of the unsaturable process for the dihydroxy bile acids was also ten times greater than that for the trihydroxy bile acids. After correction for the nonsaturable binding to the cell membrane and linear entry, the Km and Vmax for the uptake was determined. Conjugation with taurine decreased the Km of CA but not the Vmax, while glycine conjugation did not alter either parameter, suggesting that conjugation with taurine may increase its affinity for the transport system. The trihydroxy bile acids have a higher affinity but a lower transporting capacity for the saturable process than the dihydroxy bile acids. In vivo hepatic extraction appears to be more dependent on the affinity of the bile acid for the transport system than the capacity at which it can be transported.

Animals↗
PubMed1982

Hepatic extraction of bile acids in rats.

The hepatic extraction ratio (Eh) of five common bile acids was determined by comparison of the area under the plasma concentration time curve (AUC) after administration into the femoral and portal veins of rats. Taurocholic acid (TCA), glycocholic acid (GCA), cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were studied. Using equimolar doses of the bile acids (9.3mumoles), the effects of both conjugation and the number and position of hydroxyl groups on Eh were compared. TCA had the highest Eh (about 80 per cent) followed in order by GCA (65 per cent), CA (55 per cent) and CDCA (55 per cent, with DCA exhibiting the lowest Eh (40 per cent). This suggests that conjugation has a more important effect on hepatic extraction of bile acids than the number of hydroxyl groups.

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↗
PubMed1982

Action of melanophore-stimulating hormone on melanophores of the cyprinid fish Zacco temmincki.

1. Alpha MSH was extremely effective in inducing melanosome dispersion in both innervated and denervated melanophores in isolated scales of Zacco termmincki. 2. The sensitivity of the melanophores to MSH did not change after denervation. 3. The MSH action was blocked by mersalyl, a SH inhibitor, but not by any of alpha and beta adrenergic blockers. 4. Ca2+ was required for the MSH action, but not for melanosome dispersion itself, since the beta adrenergic response was normally produced in the absence of this ion. 5. Mg2+, Sr2+ and Ba2+ could not replace the Ca2+. 6. Mn2+ reversibly inhibited the MSH action.

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↗
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

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↗
PubMed1980

Effect of heparin injection on plasma protein binding of 1-anilino-8-naphthalenesulfonate and salicylate in rats.

After intravenous injection of heparin, the plasma protein binding of 1-anilino-8-naphthalenesulfonate (ANS) was remarkably decreased in rats. This effect occurred within one min after the injection of 1000 units/kg of heparin and lasted for about 30 min. The change in the binding of ANS was closely related to the plasma concentration of free acids (FFA), which was suggested as one of the heparin-induced inhibitors. The free fatty fraction of salicylate in plasma after the intravenous injection of heparin, has a pronounced variation, and also had a statistically significantly correlation with the plasma free fraction of ANS. It was suggested that ANS might be useful for the prediction of the heparin-induced changes in the plasma protein binding of acidic drugs.

Anilino Naphthalenesulfonates↗
PubMed1979

Uptake of unconjugated bilirubin by isolated rat hepatocytes.

The mechanism responsible for the hepatic uptake of unconjugated bilirubin was examined in isolated rat hepatocytes from control and phenobartital-pretreated rats. The uptake was extremely rapid and the equilibrium between cell and medium was attained within 60 s with a 100-fold higher concentration in the cell than the medium. The initial velocity of uptake (Vo) exhibited a linear relationship to the bilirubin concentration in the medium. Pretreatment of cells with various metabolic inhibitors had no effect on the uptake of unconjugated bilirubin. Ouabain did significantly decrease Vo, but replacement of sodium ion with choline or lithium had no effect on bilirubin uptake. The organic acids sulfobromophthalein (112 muM) and taurocholic acid (50 (muM) and two steroidal compounds, diethylstilbestrol (50 muM) and spironolactone (50 muM), had no effect on the uptake of bilirubin. It is suggested that bilirubin gains access to the hepatocyte interior by passive diffusion into and through the lipid membrane and that intracellular binding may explain the high degree of bilirubin accumulation associated with the isolated hepatocytes.

Animals↗