[Therapeutic drug monitoring of quinidine].
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Age Factors↗
Biomedical subjects
R Hori
Publications and source records attributed to R Hori.
Inhibitory effect of diethyl pyrocarbonate on the H+/organic cation antiport system in rat renal brush-border membranes.
We examined the effect of diethyl pyrocarbonate (DEPC), a histidine-specific reagent, on the H+/organic cation antiport system in brush-border membrane vesicles isolated from the rat renal cortex. Pretreatment of membrane vesicles with DEPC resulted in the inhibition of tetraethylammonium transport. This inhibition was reversed by subsequent treatment with hydroxylamine, but not with dithiotreitol. In contrast, the uptake of p-aminohippurate, a typical organic anion, was not inhibited by DEPC pretreatment. In the absence of an H+ gradient, pretreatment with DEPC inhibited the uptake of tetraethylammonium at pH 6.0-7.0, but not at pH 7.5. The Vmax value of tetraethylammonium uptake at pH 7.0 was decreased without any change in the Km value, but the kinetic parameters at pH 7.5 were unchanged. Unlabeled tetraethylamonium did not protect against the inhibition by DEPC. These results suggest that histidine residues in the organic cation carrier are essential for transport at acidic and neutral pH values, but not at alkaline pH values, and that histidine residues play an important role as regulatory sites in the H+/organic cation antiport system rather than as binding sites for organic cations.
Animals↗
Interaction of gentamicin with atrial natriuretic polypeptide receptors in renal cells.
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Atrial Natriuretic Factor↗
Effect of brain natriuretic peptide on cyclic GMP accumulation in a kidney epithelial cell line (LLC-PK1).
The effect of porcine brain natriuretic peptide (pBNP) on cyclic GMP accumulation was studied in the kidney epithelial cell line, LLC-PK1. The addition of pBNP to the LLC-PK1 cells produced a time- and concentration-dependent increase in cyclic GMP accumulation and this effect was equipotent to that of alpha-human atrial natriuretic peptide (alpha-hANP). The simultaneous addition of pBNP and alpha-hANP at the maximal effective concentration of 10(-6) M did not have an additive effect on the cyclic GMP contents. The findings suggest that pBNP and alpha-hANP may share the same receptor in the LLC-PK1 cells.
Animals↗
Contribution of monoamine oxidase (MAO) to the binding of tertiary basic drugs in lung mitochondria.
The effects of tertiary amine-containing basic drugs on the enzymes located in the mitochondria and the effect of monoamine oxidase inhibitors (MAOIs) on drug accumulation in lung mitochondria have been studied. Various basic drugs inhibited MAO activity but not other mitochondrial marker enzymes. The potency of MAO inhibition correlated well with their lipid solubility, and the basic drugs inhibited MAO activity dose dependently and competitively. Further, MAO inhibition correlated well with binding affinity to lung mitochondria, and the binding of tertiary amine drugs to lung mitochondria was decreased by treatment with MAOIs. A good correlation was observed between the potency of MAOIs to inhibit the binding of the basic drug to the high-affinity site in mitochondria and the MAO inhibitory activity in mitochondria. These results indicate that mitochondrial MAO is one of the binding sites for tertiary basic drugs in the lung. We think that the action and/or adverse reaction of some drugs may result from inhibition of mitochondrial MAO to metabolize various biogenic amines and that mitochondrial MAO may function as a reservoir for basic drugs.
Animals↗
Enhanced bioavailability of subcutaneously injected insulin coadministered with collagen in rats and humans.
The present study was undertaken to develop an agent that stabilizes insulin injected subcutaneously. 125I-Porcine insulin with 0.2 U/kg unlabeled porcine insulin was subcutaneously injected with or without collagen in the rat under the depilated skin of the back. At various times, the radioactivity in subcutaneous tissue was assayed for insulin and its metabolites by gel filtration. The degradation and absorption rate constants of insulin at the subcutaneous injection site were estimated according to a one-compartment model. The degradation rate constant of insulin in the presence of collagen at the injection site was less than half of the control rate. The inhibition was confirmed by increases in the immunoreactive insulin plasma levels and the hypoglycemic effect in rats and healthy volunteers. We postulate that collagen prevents insulin from being degraded by inhibiting proteolytic enzymes, mainly collagenase-like peptidase, in subcutaneous tissue.
Animals↗
Decreased transport of p-aminohippurate in renal basolateral membranes isolated from rats with acute renal failure.
Transport of D-glucose, p-aminohippurate (organic anion), and tetraethylammonium (organic cation) was studied in the renal basolateral membrane vesicles isolated from rats with acute renal failure (ARF). ARF was induced by a single injection of uranyl nitrate. Carrier-mediated transport of p-aminohippurate, estimated under anion-anion exchange condition, was significantly decreased in basolateral membrane vesicles isolated from ARF rats. In contrast, there were no significant differences in D-glucose and tetraethylammonium uptake between normal and ARF rats. When normal basolateral membrane vesicles were incubated in vitro with uranyl nitrate, no significant inhibition in p-aminohippurate uptake was observed. These results suggest that organic anion transport is decreased in renal basolateral membranes from ARF rats, and this transport dysfunction cannot be explained by the direct interaction of uranyl nitrate with the organic anion carrier.
Acute Kidney Injury↗
Pharmacokinetics and dromotropic activity of ajmaline in rats with hyperthyroidism.
1. The pharmacokinetics and the dromotropic action (increased PQ interval) of intravenously administered ajmaline (2 mg kg-1) were studied in hyperthyroid rats with sinus tachycardia. The hyperthyroidism was induced by intraperitoneal injection of 3,5,3'-triiodo-L-thyronine (0.5 mg kg-1) for 4 days. 2. The change in the ajmaline concentration in whole blood could be described by a biexponential equation. The steady state distribution volume of ajmaline decreased from 4.81 l kg-1 in control rats to 3.80 l kg-1 in hyperthyroid rats and the total body blood clearance was slightly higher in hyperthyroid rats than in control rats. 3. Ajmaline exhibited a saturable binding to rat plasma proteins, and one kind of binding site was found in the observed range of concentrations. The binding capacity was 2 fold higher in hyperthyroid rats than in control rats. 4. On the basis of the plasma unbound concentration, ajmaline exhibited an increased negative dromotropic activity in hyperthyroid rats compared with control rats. 5. A positive correlation was found between the pacing rate and the dromotropic action of ajmaline on atrioventricular conduction in isolated perfused hearts. There was no significant difference in the rate-dependence of the effect of ajmaline on the heart between control and hyperthyroid rats. 6. Our findings suggest that the increased dromotropic activity of ajmaline is mainly due to the increased heart rate in hyperthyroid rats.
Ajmaline↗
Transport of cephalosporin antibiotics in rat renal basolateral membranes.
Transport mechanisms of cephalosporin antibiotics in rat renal basolateral membranes have been studied in isolated membrane vesicles. Uptake of [14C]p-aminohippurate, a typical organic anion, by basolateral membrane vesicles was enhanced when membrane vesicles were preloaded with unlabelled p-aminohippurate (counter-transport). Cephalosporins such as cephradine, cephalexin, and cefazolin inhibited the counter-transport of [14C]p-aminohippurate, as did unlabelled p-aminohippurate and probenecid. In contrast, cephalexin did not affect the uptake of [3H]tetraethylammonium, an organic cation, by basolateral membrane vesicles. These results suggest that most cephalosporins are transported via organic anion transport systems in rat renal basolateral membranes.
Animals↗
Submitochondrial distribution of basic drugs in the isolated perfused lung.
To clarify the mechanism by which basic drugs accumulate in the lung mitochondria, the binding selectivity of drugs to different submitochondrial components of the perfused rat lung was examined. The accumulation of basic drugs was the highest in the mitochondrial outer membrane fraction. The drug accumulation in this fraction increased with lipid solubility and was dose-dependent. It appears then that selective binding sites for basic drugs are present in the mitochondrial outer membrane.
Animals↗
Effect of protein binding on the disposition of cephalexin and cefazolin in a simultaneous perfusion system of rat liver and kidney.
The effect of protein binding on the disposition of cephalexin (CEX) and cofazolin (CEZ) was investigated in a simultaneous perfusion system of rat liver and kidney. In the present study, we used bovine serum albumin (BSA) or human serum albumin (HSA) as plasma protein to control the degree of perfusate protein binding of drugs. Total clearance (CLt) of CEX perfused with BSA (0.70 +/- 0.27 ml/min) was slightly smaller than that with HSA (0.89 +/- 0.08 ml/min), corresponding to the unbound fraction of the drug in the perfusate plasma. On the other hand, CLt of CEZ perfused with BSA (0.90 +/- 0.20 ml/min) was significantly larger than that with HSA (0.32 +/- 0.10 ml/min). The unbound fraction of CEZ to BSA (0.703 +/- 0.052) was much larger than that to HSA (0.253 +/- 0.017) and the clearance of the unbound drug did not differ significantly between two kinds of albumin perfusate (1.30 +/- 0.40 ml/min for BSA and 1.26 +/- 0.40 ml/min for HSA). These results suggest that plasma protein binding is an important factor determining the biliary clearance as well as the urinary clearance of drugs.
Animals↗
Accumulation mechanism of basic drugs in the isolated perfused rat lung.
The mechanism of the accumulation of basic drugs was investigated by isolated rat lung perfusion. Treatment with various metabolic inhibitors or non-basic drugs did not affect the accumulation of a basic drug in the lung, but a second basic drug inhibited the accumulation of the first basic drug depending on its lipid solubility. The basic drug already accumulated was rapidly displaced by the second drug except for poorly lipid-soluble basic drugs and non-basic drugs. The ability of a second basic drug to displace the first basic drug was well correlated with its ability to inhibit accumulation. From the Scatchard plot, at least two independent sets of binding sites for basic drugs were found to be present in the isolated perfused lung. The maximum binding capacity for each basic drug was similar in both sites. These results indicate that specific common binding sites for basic drugs, which do not contribute to the active transport system, exist in the lung tissues and the affinity to the sites depends on the lipid solubility of the basic drugs.
Animals↗
Structure activity relationships in PIPC-analogues against Pseudomonas aeruginosa.
The relationship between the chemical structure and mode of action of piperacillin-analogues (PIPC-analogues) against Pseudomonas aeruginosa was investigated. The antibacterial activities of PIPC-analogues became stronger as the chain length of the alkyl group on the N-4 position in 2,3-dioxopiperazine when tested in constitutively beta-lactamase-producing strain, but not paralleled in wild and beta-lactamase-less strains. The outer membrane permeability was hardly affected by the chain length of the alkyl group at the N-4 position. The stability to beta-lactamase was stronger with the increase of the number of the carbon atoms of N-4 position. In the binding-affinities to the lethal penicillin-binding proteins (PBPs), compounds PIPC (C-2), C-3 and C-4 showed lower ID50 values than compounds C-1, C-6 and C-8. These results suggested that the stability to beta-lactamase was the governing part for the antibacterial activity in constitutively beta-lactamase-producing strain, and the binding affinity to lethal PBPs directly contributed to the antibacterial activity in wild and beta-lactamase-less strains.
Bacterial Outer Membrane Proteins↗
Blood oxygen tension-related change of theophylline clearance in experimental hypoxemia.
The effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O2-92% N2. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P less than .01) from 0.156 +/- 0.020 l/kg/hr in control to 0.0556 +/- 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.
Animals↗
Effect of various chemical modifiers on H+ coupled transport of cephradine via dipeptide carriers in rabbit intestinal brush-border membranes: role of histidine residues.
We examined the effect of diethylpyrocarbonate (DEPC), a histidine specific reagent, on H+ coupled transport of cephradine via dipeptide carriers in the intestinal brush-border membranes, in comparison with the effects of other chemical modifiers. Pretreatment of membrane vesicles with DEPC resulted in the inhibition of cephradine transport in the presence or absence of an inward H+ gradient. This inhibition was reversed by subsequent treatment with hydroxylamine, but not with dithiothreitol. The inactivation by DEPC pretreatment was abolished by the presence of cephradine or glycylsarcosine. In the DEPC-pretreated membranes, the V(max) value of cephradine uptake was decreased without any change in the Km value. In contrast, cephradine uptake was not changed by the pretreatment with N-acetylimidazole, a tyrosine specific reagent, or p-chloromercuribenzene sulfonate, a sulfhydryl reagent. These results suggest that histidine residues in the carriers are essential for H+ coupled transport of amiocephalosporins.
Animals↗
[Transport of organic acids in the proximal renal tubules].
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Aminohippuric Acids↗
pH sensitivity of H+/organic cation antiport system in rat renal brush-border membranes.
We examined the pH sensitivity of the H+/organic cation antiport system in brush-border membranes isolated from rat renal cortex. The uptake of tetraethylammonium, a typical organic cation, in the absence of an H+ gradient had a marked pH dependence with an optimum pH of 7.0, while the uptake of p-aminohippurate, an organic anion, and D-glucose was almost consistent in the pH range of 6.0-8.0. The decreased tetraethylammonium uptake by brush-border membrane vesicles, suspended in an acidic pH buffer or an alkaline pH buffer, was completely recovered by subsequent treatment of the vesicles with a pH 7.0 buffer. The pH sensitivity of tetraethylammonium uptake was not changed in the presence of either carbonyl cyanide p-trifluoromethoxyphenylhydrazone, a protonophore, or valinomycin (voltage-clamped condition). Kinetic parameters of tetraethylammonium uptake were changed in a pH-dependent manner, although Eadie-Hofstee plots of tetraethylammonium uptake were linear in the pH range of 6.0-8.0, indicating the existence of one mode of transport system at various pH values. At an acidic pH, the Km was increased without any change in Vmax value, compared with the values at pH 7.0. On the other hand, at an alkaline pH, the Vmax was decreased without a change in Km value. These results suggest that the H+/organic cation antiport system in renal brush-border membranes is very sensitive to pH (optimum pH of 7.0), in contrast to organic anion and D-glucose transport systems, and that pH is an important factor to regulate the activity of the H+/organic cation antiport system, as well as H+ gradient (a driving force).
Animals↗
Moment analysis of drug disposition in kidney: transcellular transport kinetics of p-aminohippurate in the isolated perfused rat kidney.
The mean renal epithelial cell residence time, Tcell, was defined as a model-independent characteristic of the transcellular transport process in the isolated perfused kidney. The transcellular transport process includes transport at the basolateral membrane, diffusion in the cytosol, and transport at the brush border membrane. The parameter Tcell represents the mean time for the drug secreted from the tubules to pass through the renal epithelial cells, and is calculated as the difference of the mean urinary transit time between secreted drug and inulin in the single-pass perfusion system. Therefore, the urinary excretion rate-time course is indispensable to evaluate Tcell. p-Amino-hippuric acid was used as a model compound. The bovine erythrocytes in the perfusate kept the isolated kidney in an almost constant physiological condition, including secretion function. The renal vein outflow curves were also analyzed by the use of moments. The dispersion in the catheter was corrected by a deconvolution. The apparent secretion intrinsic clearance and the apparent volume of distribution were calculated from the moments. The present method will be useful for analysis of the transcellular transport mechanism and the effect of disease states on renal transport of drugs.
Aminohippuric Acids↗