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PubMed1984

Tolbutamide and glyburide differ in effectiveness to displace alpha- and beta-adrenergic radioligands in pancreatic islet cells and membranes.

Previous in vivo findings indicated that alpha-adrenergic blocking agents enhanced tolbutamide-induced insulin secretion, whereas beta-blockade attenuated it. In the present study, the interaction of tolbutamide and glyburide with the rat islet adrenergic receptors is examined directly by determining the effectiveness of these drugs to displace the specific alpha- and beta-adrenergic radioligands, [3H]-clonidine and [3H]-dihydroalprenolol (DHA). It was found that both tolbutamide and glyburide had affinity constants for the adrenergic receptors that were similar to those for the natural receptor ligands and powerful antagonists. Tolbutamide displaced both alpha- and beta-radioligands but had a higher affinity at the beta-receptor. Glyburide also displaced radioligands from both types of receptors but had a higher affinity for the alpha-receptor. This study suggests that these two sulfonylurea hypoglycemic agents may affect insulin secretion by different mechanisms.

Alprenolol↗
PubMed1986

Effects of tolbutamide pretreatment on the rate of conversion of newly synthesized proinsulin to insulin and the compartmental characteristics of insulin storage in isolated rat islets.

Tolbutamide (1 g/kg body wt) was administered to male rats for 3 days to determine the effects of this pretreatment on subsequent insulin biosynthesis and compartmental storage characteristics of freshly isolated islets. Islets were isolated 16 h after the last tolbutamide administration, at a time when fed plasma glucose concentrations were normal. Islet glucagon was unchanged but insulin content was significantly reduced (38 +/- 1.2 ng IRI/islet from seven untreated rats versus 7.9 +/- 1.2 ng IRI/islet from eight treated rats). After tolbutamide pretreatment, the rate of incorporation of 3H-leucine into islet proinsulin was unchanged, but the t1/2 of labeled proinsulin-to-insulin conversion was significantly (P less than 0.001) decreased from 36 to 20 min. After treatment, actual rates of glucose-stimulated insulin secretion were 50% lower, however, because due to the proportionately greater depletion of islet insulin content, the fractional rate of secretion was increased two-fold. After treatment, there was evidence of compartmental, heterogeneous insulin storage, and glucose still marked newly synthesized insulin for preferential release; however, the differential release of new and old insulin converged rapidly with time. Mathematical integration of the data suggested dilution of the newly synthesized insulin compartment with unlabeled insulin during the chase period, but additionally indicated more rapid mixing of newly synthesized with previously stored, unlabeled insulin. Thus, tolbutamide-treated rats partially compensated for acute insulin depletion by increasing the rate of proinsulin-to-insulin conversion, but not increasing the rate of proinsulin biosynthesis; doubling the glucose-stimulated fractional secretory rate of the depleted cellular insulin storage compartment; and retaining compartmental storage characteristics but mixing newly synthesized insulin more rapidly with the compartment of previously stored, unlabeled insulin.

Animals↗
PubMed1998

Tolbutamide and diazoxide influence insulin secretion by changing the concentration but not the action of cytoplasmic Ca2+ in beta-cells.

Sulfonylureas stimulate insulin secretion by blocking ATP-sensitive K+ channels (K+-ATP channels) of the beta-cell membrane, thereby causing depolarization, Ca2+ influx, and rise in cytoplasmic Ca2+ concentration ([Ca2+]i), whereas diazoxide inhibits insulin secretion by opening K+-ATP channels. It has been suggested recently that these drugs also respectively increase and decrease the efficacy of Ca2+ on exocytosis. This hypothesis was tested here with intact islets or single beta-cells from normal mice. Depolarizing islet cells by raising extracellular K+ from 4.8 to 15, 30, and 60 mmol/l progressively raised [Ca2+]i and stimulated insulin secretion. The magnitude of the [Ca2+]i rise produced by a subsequent addition of 100 micromol/l tolbutamide decreased as the concentration of K+ was increased. The effect on insulin secretion paralleled that on [Ca2+]i. Similarly, the magnitudes of the [Ca2+]i drop and of the inhibition of insulin secretion produced by 250 micromol/l diazoxide were inversely related to the concentration of K+. Either drug was effective on secretion only when it increased or decreased [Ca2+]i. Exocytosis of insulin granules from single, voltage-clamped beta-cells was also studied by measuring cell capacitance changes. In the perforated patch configuration, exocytosis was evoked by depolarizing pulses. Addition of tolbutamide to the extracellular medium did not affect the Ca2+ current and the resulting change in cell capacitance. In the whole-cell configuration, cell capacitance increased with the concentration of free Ca2+ in the solution diffusing from the pipette into the cell. It was markedly potentiated by cAMP, was inhibited by activation of alpha2-adrenoceptors with clonidine, and was strongly augmented by acetylcholine. In contrast, tolbutamide was ineffective whether applied intra- or extracellularly, at low or high free Ca2+, and with or without cAMP. Diazoxide also failed to interfere directly with exocytosis. These results indicate that tolbutamide and diazoxide affect insulin secretion by changing the concentration, not the action, of Ca2+ in beta-cells.

Animals↗
PubMed1998

Involvement of nitric oxide (NO) in hypoglycaemic activity of tolbutamide.

The study was conducted to find the involvement of Nitric Oxide (NO) using L-arginine, a NO precursor and NG-methyl L-arginine a nitric oxide synthase inhibitor on tolbutamide activity in normal rabbits. L-arginine (25-300 mg/kg, body weight, oral) produced transient and dose dependent hypoglycaemia. When combined with tolbutamide (40 mg/kg, oral) it produced early and prolonged action. The effect of tolbutamide was blocked by NG-methyl L-arginine (5 mg/kg, body weight, oral). The results confirm the involvement of NO in tolbutamide activity and the possibility of using L-arginine as a supplement to antidiabetic drugs in blood glucose control.

Animals↗
PubMed2002

Hypoglycemic and hypotriglyceridemic effects of tolbutamide in triphenyltin chloride-induced diabetic rabbits.

Triphenyltin (TPT) induces transient hyperglycemia and hypertriglyceridemia in rabbits and hamsters through inhibition of the insulin release stimulated by glucose. The disturbed site in TPT-diabetes is a result of signal transduction occurring before the voltage-dependent Ca2+ channel. The ATP-sensitive K channel (KATP channel) is located immediately at the upstream signal of voltage dependent Ca2+ channels on the signaling pathway of insulin secretion. KATP channel produces depolarization by a signal of ATP through glucose metabolism and by stimulation from sulfonylurea drugs (tolbutamide, glibenclamide). To clarify if the insulin secretion that a KATP channel mediates is inhibited in vivo, we studied the effects of tolbutamide (a sulfonylurea) on changes in plasma glucose, triglyceride and insulin in TPT-diabetic rabbits prepared by po administration of 100 mg TPT-chloride/kg bw. In TPT-diabetic rabbits, plasma glucose decreased to a minimum at about 50% and plasma triglyceride levels also decreased. Insulin release was detected after injecting = 10 mg tolbutamide/kg, and insulin was secreted much higher than in normal rabbits. These findings suggest that the insulin released by tolbutamide stimulus decreased the plasma glucose and triglyceride levels in the TPT-diabetic rabbits. Moreover, a possible mechanism to be considered is as follows: tolbutamide combines with sulfonylurea receptor; membrane depolarization is induced by a KATP channel with the signal of a sulfonylurea receptor; insulin is released. The inhibition of insulin secretion by TPT may be caused by a glucose metabolic disorder in beta cells before the occurrence of membrane depolarization due to closed KATP channels interacting directly with a sulfonylurea receptor.

Administration, Oral↗
PubMed1958

Oral administration of orinase (tolbutamide); clinical observations of effect on nondiabetic and diabetic humans.

Ingestion of tolbutamide (Orinase(R)) by nondiabetic humans brought about a maximum reduction in blood sugar within one to two hours. In diabetic persons taking large doses of insulin, or who needed insulin for control, hyperglycemia, ketosis, and increased excretion of glucose in the urine developed when tolbutamide was substituted for insulin or was used before insulin therapy was begun. The only serious toxic manifestation observed was a skin rash in two patients. Successful control of diabetes with tolbutamide was limited to cases in which the disease was of mild, stable type and the patient was 40 or more years of age, of normal weight, and with a previous insulin requirement of 5 to 30 units per day. It was of benefit in 43.5 per cent of all diabetic patients in the series studied and in about 75 per cent of the group that might be referred to as selected. The duration of the disease and the duration of insulin therapy were unimportant in predicting effectiveness for tolbutamide therapy.

Administration, Oral↗
PubMed1992

Co-regulation of phenytoin and tolbutamide metabolism in humans.

1. The disposition of phenytoin and tolbutamide was compared in eighteen healthy young adults separately administered single therapeutic doses (sodium phenytoin 300 mg, tolbutamide 500 mg) of the two drugs. 2. Within the group, ratios of ranges of total and unbound areas under the plasma concentration-time curves were similar for both drugs. 3. There were significant (P < 0.001) correlations between total (r = 0.88) and unbound (r = 0.86) areas under the plasma phenytoin and tolbutamide concentration-time curves. 4. The results are consistent with the involvement of the same cytochrome P-450 isoenzyme(s) in the metabolism of tolbutamide and phenytoin.

Adult↗
PubMed1991

[Evaluation of hepatic microsomal enzyme activity using C-l4-labeled aminopyrine breath test in patients with diabetes mellitus type 2 treated with tolbutamide].

Among 116 diabetic patients of the District Diabetic Polyclinic in Zabrze (51 type II treated with tolbutamide++, 36 type I treated with insulin, 29 type II treated with diet only) and 30 health persons functional microsomal hepatic fraction with ABT was assessed. Classical hepatic function test were done too. Among 49% patients under examination with type II diabetes treated with tolbutamide++ statistically significant decrease of value of ABT was observed as compared with other groups. Values of classical hepatic function tests in investigated patients were within normal values. Decrease in demethylation of aminopyrine shown as the abnormality in values of ABT can be considered as early symptom of hepatocyte damage caused by tolbutamide++. ABT is valuable method of appraising the liver's detoxication function in type II diabetes. Patients treated with tolbutamide++ should not receive any other drug known as inhibitor of microsomal enzymes of the liver.

Adult↗
PubMed1991

[Improvement in glucose tolerance and insulin sensitivity after a single administration of tolbutamide in hypertensive patients].

In a group of 19 patients selected at random, suffering from hypertension and signs of atherosclerosis of the coronary vessels glucose intolerance was revealed in 10 patients. Comparisons disclosed: a) Levels of immunoreactive insulin (IRI) rose more and declined more slowly in patients with glucose intolerance than in patients with glucose tolerance. b) The ratio IRI/glucose in plasma of patients with glucose intolerance increased less than in patients with satisfactory tolerance. c) 500 mg tolbutamide by the oral route reduced the blood sugar level during the first and second hour following administration of 75 mg glucose substantially more in patients with glucose intolerance. d) Tolbutamide reduced at the same time intervals also the rise of IRI levels, approximately equally in both groups of patients. e) Tolbutamide increased the IRI/glucose ratio during the investigated intervals. The authors conclude that a direct influence on glucose utilization in peripheral tissues is involved and an increased insulin sensitivity of skeletal muscles and other tissues after tolbutamide.

Blood Glucose↗
PubMed1968

Effect of insulin and tolbutamide on growth rate, blood glucose and body composition of lambs.

Twenty-four 8 to 9-week old lambs were used in each of two experiments. They were fed ad libitum a pelleted ration containing 30% hay and 70% concentrates. Blood glucose was determined on half of the lambs in each experiment every second week at 0, 4, 8 and 24 hrs after treating with insulin or tolbutamide. In the first experiment, protamine zinc insulin given subcutaneously every second day at levels of 0.2 and 1.0 I.U./kg of body weight, had no significant effect on blood glucose level, growth rate or carcass composition. In the second experiment, tolbutamide and insulin were given to different groups of weanling lambs with the dosage increased every 2 weeks until signs of hypoglycemia began to appear. The dosage was then kept at this level until the lambs reached market weight. A significant decrease in blood glucose was observed in both groups of lambs at six weeks when the dosage of tolbutamide reached 120 mg/kg and the insulin reached 40 I.U./kg. Lassitude and anorexia were observed in one lamb receiving insulin. Neither treatment significantly affected growth rate or carcass composition. It was concluded that supplemental insulin or tolbutamide are of no value in fattening lambs.

Animal Feed↗
PubMed1977

[Tolbutamide as a stimulator of somatotropin secretion from the hypophysis].

Our clinical experiments should point at the potential quality of tolbutamide as a stimulator of the secretion of the growth hormone. This could not be ascribed to the hypoglycaemic action of tolbutamide, because during the 240 minutes' time of the duration of the test, the glycaemic levels in the blood have been kept stabilised at the same levels as in fasting conditions before the application of tolbutamide, by a continuous intravenous drop of a 10% solution of glucose. The values of the growth hormone after application of tolbutamide raised two to fourfold in comparison to the initial value.

Blood Glucose↗
PubMed1977

Response of plasma insulin to small doses of tolbutamide in obesity and acromegaly.

The early response of plasma insulin (IRI) to successive intravenous doses of 50, 100 and 200 mg of tolbutamide was studied in nondiabetic obese subjects, in acromegalic patients, and in healthy controls. The smallest dose raised the plasma IRI level within two minutes in all subjects. The insulin response was correlated with the basal IRI in controls and in obese subjects but not in acromegalic patients. At each tolbutamide dose level the mean IRI response of obese subjects was about three times greater than in controls. In acromegalic subjects an increased response was observed only after the 200 mg dose of tolbutamide. The results suggest that in obesity the stimulus-secretion coupling of insulin output is normal but the number of secretory units is increased. In acromegaly the insulin release pattern is compatible with an increased number of secretory units which, however, are relatively insensitive to tolbutamide, probably due to an elevated serum growth hormone level.

Acromegaly↗
PubMed1982

Potentiation of insulin and tolbutamide of the effect of indomethacin on carrageenan paw edema in the rat.

The influence of insulin, tolbutamide and buformin on the effect of indomethacin as measured in the carrageenan paw edema assay in Sprague-Dawley rats has been studied. Small doses of these agents, having no influence on edema formation when given by themselves, were tested in combination with indomethacin. Insulin and tolbutamide potentiated the effect of indomethacin in the early phase of carrageenan paw swelling (2 hr), while they did not significantly alter the late phase (5 hr). Buformin was ineffective at any time. Insulin and tolbutamide in the doses applied moderately lowered blood sugar level, whereas buformin did not, thus tolbutamide-induced potentiation may be due to insulin release. No change in blood pressure of rats was observed under treatment. The possible mechanism of the supra-additive effect of insulin and indomethacin on the edema formation induced by carrageenan is discussed.

Animals↗
PubMed1980

Interaction of phenylbutazone and tolbutamide in man.

Phenylbutazone pretreatment increases tolbutamide half-life, whereas tolbutamide pretreatment decreases phenylbutazone half-life in man. Clinically, phenylbutazone may enhance the hypoglycemic action of tolbutamide, and tolbutamide may reduce the therapeutic effect of phenylbutazone.

Adult↗
PubMedDate not supplied

[Changes in insulin (IRI) and NEFA levels in diabetic subjects after acute intravenous glipizide and tolbutamide administration].

Glypizide and i.v. tolbutamide were administered to a series of diabetics. On different days, 10 subjects (controls for themselves) received 1 mg glypizide anal 100 mg tolbutamide; a further 10 received 2 mg glypizide and 200 mg tolbutamide. Blood sugar and insulin and NEFA values were determined every 10' for one hour after the injection. It was found that the hypoglycaemising activity of glypizide was about 140 times that of tolbutamide. It also caused a greater incretion of insuline and a more marked reduction of NEFA.

Aged↗
PubMed1997

Bioequivalence of tolbutamide-containing tablet preparations.

The present crossover study was undertaken to investigate in 22 volunteers (15 males, 7 females, aged 22-28 years) whether the 2 tolbutamide preparations (tolbutamide R.A.N. vs. rastinon Hoechst) are bioequivalent. After administering a single dose of one 1 g tablet of each preparation the plasma tolbutamide concentration was measured by HPLC over a time-period of 48 hours. The mean AUC0-48 values are nearly identical (998.42 vs. 997.73 micrograms x h x ml-1), while the Cmax values (51.1 vs. 58.8 micrograms/ml) and the tmax values (4.55 vs. 3.82 h) show slight differences. The Westlake intervals claimed to prove bioequivalence lies in the 95% confidence interval between the limits 0.972 and 1.046 (AUC), 0.896 and 0.978 (Cmax), and 0.056 and 1.346 (tmax). For example, this is the result of the parametric analysis considering the randomization. In the case of the parameters of the multiplicative model (AUC and Cmax) the probability of correctly concluding bioequivalence (power) between the 2 preparations reaches 2.0. Regarding maintenance therapy it is of minor importance that the maximum plasma tolbutamide concentrations is 0.7 h later observed with the test preparation than with the standard. The results of this study allow the conclusion that the 2 tablet preparations are bioequivalent.

Administration, Oral↗
PubMed1976

Influence of some salicylates and sulfonamides on binding by albumin of SPC-703 and tolbutamide.

Bovine serum albumin has two different binding sites for sulfonylurea. The sites at high affinity can bind up to 2 moles of a new hypoglycemic sulfonylurea SPC-703 (k1=6.8.10(3) M(-1)) or tolbutamide K1=19.3.10(3) M(-1)). The sites of lower affinity can bind 4 mole of SPC-703 (K2=1.6.10(3) M(-1)) or 8 moles of tolbutamide (k2=1.3.10(3) M(-1)). Binding of SPC-703 and tolbutamide was decreased mostly in the presence of sulfadimetoxine, but this sulfonamide increased the concentration of free tolbutamide more than that of SPC-703.

Animals↗
PubMed1976

Extraction and partition chromatography of tolbutamide as ion-pairs with quaternary ammonium cations.

The partition of tolbutamide (1-butyl-3-(p-tolylsulfonyl) urea) as ion-pairs with homologous tetraalkyl ammonium cations was studied. The determination of experimental extraction constants permitted quantitative calculation of distribution ratios, in agreement with theoretical relationships, over a continuous range of about one billion. The nature and the concentration of the counter-ion and solvent composition were the variables studied. Based on the theoretical results, a rapid partition chromatographic procedure was devised. A solution of tolbutamide sample in 10% aqueous tetraethyl ammonium hydroxide is incorporated in the system as the immobile phase in the partition column. A 1+1 mixture of chloroform and isooctane removes extraneous materials; then chloroform elutes the tolbutamide-tetraethyl ammonium ion-pair, which is converted to the free acid by passing the eluate through a phosphoric acid segment, and tolbutamide is determined spectrophotometrically without further treatment. Standard recoveries averaged 100.5+/-0.70%; commercial tablets assayed 100.5+/-0.85%.

Biological Availability↗