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PubMed1990

Kinetic studies on drug disposition in rabbits. III. Effect of tolbutamide on renal excretion of sulfamethizole.

The effect of tolbutamide (TB) on the urinary excretion of sulfamethizole (SMZ) under constant infusion of SMZ at 100 mg/h was studied. Intravenous administration of TB (50 mg/kg) caused a decrease in the urinary excretion rate of SMZ but an increase in the unbound concentration of SMZ in plasma. The total concentration of SMZ in plasma decreased rapidly after TB injection and then increased gradually to a level higher than the control. The slope of the terminal phase of the unbound concentration of TB in plasma in the presence of SMZ was significantly smaller than that of TB alone. The analysis using the perfusion limited model showed that the elimination kinetics of SMZ in the presence of TB could be described by the mutual displacement of plasma protein binding of both drugs and the competitive inhibition of the tubular secretion of SMZ by the unbound concentration of TB in renal vein. Further the inhibitor constant was in good agreement with that for the in vitro uptake by renal cortex slices.

Animals↗
PubMed1998

Binding position of tolbutamide to human serum albumin.

The interaction between drugs (tolbutamide (1), 1-butyl-3-(methylsulfonyl)urea (2)) and human serum albumin (3) was investigated by equilibrium dialysis and NMR spectroscopy. The binding of 1 and 2 to 3 was concluded to be hydrophobic and hydrophilic, respectively, on the basis of the dependence of the binding constants on temperature, ionic strength, and chain length of fatty acid added. In 1H-NMR spectra of 1, there were no significant shifts with change in concentration or addition of 3. The spin-lattice relaxation time (T1) and spin-spin relaxation rate (1/T2) of the respective protons of 1 were independent of concentration, but depended on the concentration of 3 added. The binding position was determined from the ratio of 1/T2 of 1 bound to 3 and free 1. 1 and 2 were found to bind to 3 through the tolyl group and sulfonylurea group, respectively. The binding property of 1 was considered to be governed by the competition between the hydrophobic effect of the tolyl group and the hydrophilic effect of the sulfonylurea group in the molecule.

Binding Sites↗
PubMed2000

Study of tolbutamide-hydroxypropyl-gamma-cyclodextrin interaction in solution and solid state.

Tolbutamide-hydroxypropyl-gamma-cyclodextrin (TBM-HPGCD) interaction has been investigated in an aqueous environment and in the solid state. The solubility of TBM was increased in accord with the amount of HPGCD added to the aqueous medium forming a soluble inclusion compound. The phase solubility diagram obtained was of A(L) type. Physical mixtures and kneaded systems of the drug and cyclodextrin derivative were prepared in 1:1 and 1:2 drug/cyclodextrin mol/mol ratio. All solid binary systems were characterised by hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG) and X-ray powder diffractometry (XRD). An inclusion complex was formed in both of the kneaded systems. In the 1:2 kneaded system, the entire drug was included in the cyclodextrin cavity, while, in the 1:1 kneaded system only a part of the drug formed an inclusion complex with the cyclodextrin. A significant improvement in the dissolution of the drug was obtained from the kneaded systems in comparison with that of the pure TBM and physical mixtures. However, there was no significant difference between the dissolution profiles of the two kneaded systems. The study suggests that an inclusion complex was obtained both in aqueous solution and in solid state.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1978

[Effects of oral hypoglycemic agents, gliclazide and tolbutamide, on the cardiovascular system (author's transl)].

Recent clinical studies have suggested an association of tolbutamide (TB) therapy with an increased incidence of cardiovascular deaths. In this study, the effects of a newly synthetized hypoglycemic agent, gliclazide (GC), on the cardiovascular system were investigated, and compared with those of TB. Results are as follows: GC was found to be about ten times as active as TB in decreasing blood glucose in rabbits. GC and TB produced a dose-dependent increase in blood pressure and little change in heart rate in rats and rabbits. In driven left rat and rabbit atria, these agents produced a positive inotropic effect. The positive inotropic effects of these drugs were not altered by pretreatment with propranolol, or theophylline. These agents produced little change in the rate in spontaneous beating rat, rabbit and guinea pig atria. Higher doses produced a slightly negative chronotropic response. Neither agent potentiated the intropic effects of isoproterenol on the rabbit and guinea pig left atria. In isolated perfused working rabbit hearts, these compounds produced a slight decrease in coronary flow. It is concluded that GC and TB possess positive inotropic effects on isolated atria, and these effects are not mediated either through adrenergic mechanisms or the cyclic AMP system.

Animals↗
PubMed1976

Studies on the mechanism of somatostatin action on insulin release in man. II. Comparison of the effects of somatostatin on insulin release induced by glucose, glucagon and tolbutamide.

Somatostatin in as small a dose as 70 mug given over a period of 90 min to seven healthy subjects inhibited insulin release induced by glucose (500 mg/kg as a bolus + 20 mg/kg/min). This inhibition seemed to be of competitive nature since the effect was nearly overcome when the glucose dose was raised considerably. Somatostatin in nine subjects also inhibited insulin release induced by glucagon and tolbutamide, and this inhibition was of the same order of magnitude as that of glucose induced insulin release. Since all these insulinogogues enhance of the accumulation of cyclic AMP in the beta-cells, it is suggested that the edenylate cyclase-cylic AMP system might be involved in the action of somatostatin. Somatostatin did not seem to interfere with the glycogenolytic effect of glucagon on the liver.

Adult↗
PubMed1997

Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM.

Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.

Adenosine Triphosphate↗
PubMed1978

Studies on the effect of tolbutamide, glibenclamide, HB 699, and glucose on serum insulin and blood glucose in gastro-enterectomized dogs.

The influence of intravenously administered tolbutamide, glibenclamide, HB 699, and glucose on serum insulin and blood glucose kinetics was examined in 36 enterectomized dogs. The substances induced an immediate and long-lasting insulin release even in the absence of all insulinotropic intestinal mediators. Maximum and mean insulin concentrations after treatment, measured for 180 minutes, were markedly higher in resected dogs than in sham operated or non-operated animals. The data suggest that intestinal mediators might be of no importance in vivo for the insulin-releasing activity of the compounds examined, at least in dogs.

Animals↗
PubMed1975

Decisive factors in the tolbutamide controversy.

No increased mortality trend attributable to tolbutamide is shown by an analysis of variance on logit-transformed data from the University Group Diabetes Program (UGDP) study. The UGDP's controversial finding of an increased rate with mortality subgrouped by "cardiovascular" causes is confirmed by the Biometric Committee's report, with reservations that failed to include overriding decisive factors. The basic problem is that inspected data set up the hypothesis (the increased cardiovascular mortality), and that the same data were used to test the hypothesis, so that resulting probability values no longer have the usual meaning. The problem was compounded by multiple testing of the data without adjusting the probability levels. When cardiovascular deaths were redefined as myocardial infarcts and sudden deaths, in an attempt to test a proposed etiologic inotropic hypothesis, no significant increase in cardiovascular mortality was found.

Age Factors↗
PubMed1992

[X-ray diffraction studies on tolbutamide solid dispersion].

D860 (tolbutamide) solid dispersions prepared with urea, polyvinyl pyrrolidone (PVP), and polyethylene glycal (PEG) 6000 as carriers were studied by X-ray diffraction, relating to their dissolution rates. D860 in D860-PVP dispersion was shown to be in an amorphous state and to have greater dissolution rate. D860-urea and D860-PEG melts were found to be partly in miscible solid solution state and partly in microcrystal state and possess higher activity and greater dissolution rate. D860-PEG coprecipitate was a physical mixture and its dissolution rate is slower than its melt. No variation in the crystal structure of the D860 dispersions was observed during the ageing test.

Drug Carriers↗
PubMed1992

Six-base deletion occurring in messages of human cytochrome P-450 in the CYP2C subfamily results in reduction of tolbutamide hydroxylase activity.

We isolated and expressed a clone, hPA6, possibly corresponding to the CYP2C9 cDNA. Compared with the other CYP2C9 cDNA clones, hPA6 showed a 6-nucleotide deletion near its middle. From the same cDNA library, we could also isolate another cDNA clone, named hPA22, which retained the 6 bases. For clarification of the effect of the 2-amino acid deletion resulting from the 6-base deletion on enzymatic activities, both clones were expressed in yeast. The expressed enzymes showed tolbutamide hydroxylase activities, and these activities were inhibited by antibodies against P-450-HM2, a probable CYP2C9. The activity of the enzyme encoded by hPA6 was lower than that encoded by hPA22; thus the 2-amino acid deletion in the CYP2C9 reduced the enzymatic activity.

Amino Acid Sequence↗
PubMed1991

Effects of glibenclamide and tolbutamide on ischemia- and ouabain-induced arrhythmias and membrane potentials of ventricular myocardium from rat and guinea pig.

Glibenclamide (Gli) 0.3, 1, 3 mg.kg-1 and tolbutamide (Tol) 3, 10, 30 mg.kg-1 iv 10 min before ischemia or ouabain infusion prevented ventricular fibrillation induced by ischemia in rat and arrhythmias induced by ouabain in guinea pig. Gli 10 mumol.L-1 and Tol 1 mmol.L-1 increased APD and ERP in rat ventricular muscle. Gli 0.1, 1, 10 mumol.L-1 and Tol 0.01, 0.1, 1 mmol.L-1 prevented and reversed the shortening of APD and ERP induced by hypoxia in guinea pig ventricular muscle. These effects of Gli and Tol were dose-dependent. The results confirmed that Gli and Tol were effective on arrhythmias induced by ischemia and ouabain by blocking ATP-sensitive potassium channel.

Animals↗
PubMed1991

Hyperpolarization of denervated skeletal muscle by lemakalim and its antagonism by glybenclamide and tolbutamide.

Innervated skeletal muscles are endowed with K+ channels activatable by K+ channel openers. It is of interest to know whether the denervation-induced depolarization is due to a deficiency of such a K+ channel. In denervated mouse diaphragm, lemakalim, a K+ channel opener, effectively hyperpolarizes membrane and reduces membrane resistance, spontaneous activity as well as twitch force reversibly. Reductions of transmembrane K+ gradient diminish the lemakalim-induced hyperpolarization. In voltage-clamped fiber, lemakalim induces a long-lasting outward current. A current clamp experiment suggests a reversal potential of around -90 mV. On innervated diaphragm, lemakalim hyperpolarizes membrane and increases conductance if the muscle is predepolarized by anodal current. Lemakalim, however, is much less effective in overcoming the depolarization caused by crotamine, which activates Na+ channel. The effects of lemakalim are not attenuated by blockades of membrane Na+, Ca++ and Cl- permeabilities. Glybenclamide and tolbutamide, blockers of ATP-regulated K+ channel, antagonize the effects of lemakalim at low concentrations and produce slight membrane hyperpolarizations in denervated muscle, but marked membrane depolarizations in innervated muscle at higher concentrations. Cs+ depolarizes both innervated and denervated diaphragms and reduces the hyperpolarizing effect of lemakalim. The results suggest that lemakalim hyperpolarizes denervated muscle via glybenclamide sensitive K+ channels. It is inferred that a reduction of membrane K+ conductance rather than an increase of Na+ or Ca++ conductance contributes to the denervation-induced depolarization.

Animals↗
PubMed1988

[Effect of tolbutamide on the activity of transglutaminase].

Five obese patients were studied during 7 days, 750 mg of tolbutamide, per os, was given. Blood samples were drawn at basal state and at 3, 5, 7 days during the treatment and 6 days after it. The values of transglutaminase activity (that in the basal state were similar to that in the controls) decreased significantly at the seventh day of treatment (72.3%). This decrease was transient and rapidly returned to the basal values when the drug was suspended. The results suggest that sulfonylureas exert in part their hypoglucemic effect by modificating the insulin receptor binding through the inhibition of transglutaminase activity.

Adult↗
PubMed1987

The hypoglycemic sulfonylureas glyburide and tolbutamide inhibit fatty acid oxidation by inhibiting carnitine palmitoyltransferase.

The hypoglycemic sulfonylureas glyburide and tolbutamide were found to be excellent inhibitors of the rat liver, heart, and skeletal muscle carnitine palmitoyltransferases, but glyburide was by far the most potent inhibitor. Carboxytolbutamide, a sulfonylurea that has no hypoglycemic effect, produced little or no inhibition of the enzyme from the three tissues examined. Fasting decreased the degree of inhibition of carnitine palmitoyltransferase by the sulfonylureas, and in genetically diabetic BB Wistar rats, a decrease in sensitivity was also clearly demonstrated. Initial rate kinetics of the inhibition of carnitine palmitoyltransferase indicated that glyburide inhibits noncompetitively with respect to palmitoyl-CoA while inhibition by malonyl-CoA was cooperatively competitive. Inhibition by malonyl-CoA was noncompetitive with respect to carnitine, but inhibition by glyburide was uncompetitive. These studies indicate that the hypoglycemic sulfonylureas inhibit carnitine palmitoyltransferase by a mechanism that is much different from inhibition by malonyl-CoA, but are, nevertheless, potent inhibitors of the enzyme. These results have important implications for energy metabolism in the liver and heart in relation to the use of sulfonylureas and for understanding the mechanism by which the sulfonylureas act to lower blood glucose, but there are also important implications of these results on the study of the metabolic regulation of fatty acid oxidation.

Acyltransferases↗
PubMed1979

The effects of oleic acid, tolbutamide, and oxyphenbutazone on the binding of warfarin by human serum albumin.

Equilibrium dialysis studies showed that, at low levels, stearate, palmitate and oleate enhanced the binding of warfarin by human serum albumin, but at high levels of FFA, warfarin was displaced. Tolbutamide and oxyphenbutazone separately desplaced warfarin, and this dispplacement was reduced by the presence of low concentrations of oleate while at higher concentrations of oleate displacement occurred. Thus, the binding of warfarin was affected in a complex fashion depending upon the drugs present and the concentration of the FFA.

Binding, Competitive↗
PubMed1979

[Intravenous tolbutamide test in depression].

The intravenous tolbutamide test (ORABET) shows pathological developments in timid and depressive patients, regardless of their nosological classification as suffering from unipolar endogenic depressions, the depressive phase of MDK and reactive depressions. With the disappearance of the depressive--timid psychopathological picture the i.v. TT also normalizes.

Adjustment Disorders↗