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PubMed1991

[Tolbutamide and burn hypermetabolism].

Comparatively low level of serum insulin and tissue insulin resistance are characteristic of the stage of burn hypermetabolism. In order to evaluate the effect of tolbutamide in reducing burn hypermetabolism rate, 18 adult male rabbits weighing 1.8-2.5 Kg were subjected to 30% TBSA full thickness burns and randomized into treated and control groups. In the treated group, tolbutamide (90mg/Kg/day) was introduced into the stomach from 4 hours to 10 days postburn. Animals of both group were fed with specified food (protein 15%, glucose 80%) after burn. The values of serum glucose, insulin, glucagon, oxygen expenditure and other nutritional indices were measured before burn and 1, 3, 6, 10 days postburn. Their changes were as follows: (1) Serum glucose levels of the treated group were obviously lower than those of the control group (P less than 0.01). (2) Serum insulin levels and the ratio of I/G (insulin/glucagon) of the treated group were significantly higher than those of the control group (P less than 0.01). (3) The indices of cumulative N balance, oxygen expenditure, serum albumin in the treated group were better than that in the control (P less than 0.05-0.001). It is concluded that tolbutamide can reduce burn hypermetabolism probably through the following ways: 1. stimulation of the secretion of insulin and enhancement of the effect of insulin; 2. inhibition of the secretion of glucagon; 3. improvement in tissue insulin resistance and promotion of glucose utilization of skeletal muscles.

Animals↗
PubMed1989

Modulation of A and B cell functions by tolbutamide and arginine in the pancreas of thiamine-deficient rats.

The effects of administration of glucose orally and tolbutamide or arginine intravenously on insulin and glucagon secretion and blood glucose level were studied in normal and thiamine-deficient rats. In thiamine deficiency, insulin secretion and glucose tolerance were impaired during glucose ingestion. Tolbutamide decreased the blood glucose level in both control and thiamine-deficient rats but its stimulatory effect on insulin secretion was minimal in thiamine-deficient rats unlike the control animals. Arginine did not alter substantially the blood glucose or insulin in thiamine-deficient rats, whereas it increased the insulin level in control rats. The fasting plasma glucagon level was high in thiamine deficiency. Tolbutamide increased the plasma glucagon in control rats, but did so only marginally in thiamine-deficient rats. Arginine also increased the glucagon secretion throughout the period of study in control rats. In thiamine-deficient rats the glucagon secretion was pronounced only after 20 min of arginine administration. These results suggest that an unimpaired glucose metabolism is a prerequisite to induce proper insulin secretion. Only proper insulin secretion can check the glucagon secretion rather than the increased glucose level. Hypoglycemia can induce glucagon secretion independent of the insulin level.

Animals↗
PubMed1978

[Insulin and pro-insulin secretion following intravenous administration of tolbutamide, glisoxepide and glibenclamide].

12 metabolically healthy subjects were i.v. administered equipotent doses (ED30) of tolbutamide (7.5 mg/kg), glisoxepide (0.02 mg/kg) and glibenclamide (0.006 mg/kg). Prior to and 2, 5, 8, 10, 20, 40, 60 and 120 min after the injection the following serum parameters were determined: blood glucose, immunologically measurable insulin (IMI) with the double-antibody method (Hales and Randle) and proinsulin (IMP) enzymatically (ISP-method). The maximum level of insulin follows the injection of tolbutamide with a value of 70.5 micronU/ml after 2 min, of glisoxepide after 5 min (67.0 micronU/ml) and of glibenclamide after 20 min (32.3 micronU/ml). The proinsulin fraction of the total insulin shows a level of 12.5 micronU/ml before the test. After the administration of the three compounds proinsulin increases, too, but reaches only 20-40% of the total immunoreactive insulin. The amount of secreted insulin and proinsulin during the 120-min test is rather the same for the three substances. The average increase of insulin is nearly identical for tolbutamide and glisoxepide, whereas it is less for glibenclamide. Both the mean blood sugar depression and the highest mean increase of proinsulin is reached after glisoxepide. The significance of the one-chain precursor of insulin as a part of the sulfonylurea stimulated total insulin for glucose depression is discussed.

Blood Glucose↗
PubMed1979

[Influence of allopurinol on the half-life of tolbutamide and rifamycin-SV in blood of healthy volunteers].

The influence of treatment with allopurinol (5 mg/kg/die for 15 days) on T/2 of tolbutamide and rifomycin-SV intravenously administered, has been studied in 10 healthy volunteers. We have observed reduction of T/2 of tolbutamide and, on the contrary, prolongation of T/2 of rifamycin-SV. Tolbutamide behaviour was unexpected, considering that other Authors had previously found inhibition of metabolic degradation of other drugs metabolized by the microsomal enzymes. We conclude that data concerning the influence of a drug (in our case, allopurinol) on the metabolism of another drug cannot always authorize general deduction and previsions regarding the metabolic interferences on the pharmacokinetics of other substances.

Adult↗
PubMed1979

[Intravenous administration of insulin and tolbutamide. A mathematical simulation on the different glycolytic activity in the organism (author's transl)].

A system theoretical model is developed for the different effects on the glucose metabolism after i.v. insulin injection and after the release of endogenous insulin release induced by sulfonylurea derivates. The model is based on our clinical results on the change of blood glucose and blood lactate levels after application of insulin or tolbutamide, resp.: Concerning the blood glucose depressing effects equivalent concentrations of insulin and tolbutamide cause an increase of lactate and pyruvate to different extents in healthy subjects. Possible reasons for this behaviour could be additional insulin-independent effects of tolbutamide on the glucose metabolism. The mathematical simulation of glycolysis stimulation as dynamical system with 6 variables and 14 parameters can demonstrate that a different insulin distribution in the blood circulation is sufficient to explain the different glycolytic activities. Simply the different paths of insulin entrance--either evenly distributed in the blood or directly at liver entry--may cause the different increases of lactate levels. The calculations of the time courses between 0 and 60 min after injection are in close agreement with experimental findings.

Blood Glucose↗
PubMed1979

[Interaction between naproxen and tolbutamide on metabolism in diabetics].

In a double blind study 16 maturity onset diabetics were treated with d-2-(6-methoxy-2-naphthyl)-propionic acid (naproxen) and tolbutamide with a view to possible interactions between both drugs. There were no significant differences between blood glucose levels after placebo and naproxen, respectively. The concentrations of tolbutamide were not significantly different, either. Thus diabetics on tolbutamide can be treated additionally with naproxen without any clinical side effect on carbohydrate metabolism.

Adult↗
PubMed1984

Effect of sulphonylurea derivatives, SPC-703 and tolbutamide, on insulin binding by isolated rat adipocytes.

The effect of oral hypoglycaemic drugs, SPC-703 [n-(p-toluenesulphonyl)-5-methyl-2-pirazoline-1-carbonami de] and tolbutamide on insulin binding by rat adipocytes from epididymal fat pads were studied. SPC-703 and tolbutamide in concentration of 1 mM added in vitro to the suspension of adipocytes had no effect on insulin binding and kinetic parameters of insulin receptors. Daily administration of 300 mg/kg body weight of SPC-703 or tolbutamide for 10 days resulted in 48% and 34% increase of specific binding of insulin by adipocytes, respectively. From the Scatchard plot it appears that the increase of binding resulted from increased affinity of insulin receptors. These results may explain extrapancreatic action of sulphonylurea derivatives.

Adipose Tissue↗
PubMed1982

Inotropic and electrophysiological effects of tolbutamide in normal subjects.

The acute cardiac effects of tolbutamide on myocardial contractility, evaluated with systolic time intervals (ST), and on the atrio-ventricular conduction system have been studied in a group of five volunteer normal subjects. The intravenous administration of 1 g of tolbutamide showed no considerable changes of STI and of electrophysiologic parameters. Glycemia decreased whereas there was a statistically significant increase in plasmatic levels of catecholamines at the 10th and 20th min. Our findings suggest that the intravenous administration of tolbutamide has no effect either on the atrio-ventricular conduction system or on myocardial contractility in normal men.

Adult↗
PubMed1980

Lot-to-lot variation in dissolution of tolbutamide tablets.

The dissolution characteristics of tolbutamide tablets made by two manufacturers were compared. Six tablets selected from six lots of each manufacturer were subjected to the USP rotating-basket and paddle-stirrer dissolution tests. Samples were drawn after 10, 20, 30, and 45 minutes for the rotating-basket test and after 10, 20, and 30 minutes for the paddle-stirrer test. Drug concentrations of the dissolution samples were measured by ultraviolet spectroscopy or high-pressure liquid chromatography. All lots passed the disintegration, assay, content uniformity, and tablet weight variation tests; however, there was considerable interlot and intralot variation in the dissolution characteristics of the tablets. The range of interlot differences in the average amount of tolbutamide dissolved using the rotating-basket test was 55.6% for one manufacturer's product and less than 1% for the other's. The ranges were 40.5% and 2.4%, respectively, using the paddle-stirrer test. Similar differences for intralot variation between the two manufacturers' products also existed. Constant patient monitoring appears prudent when products with highly variable dissolution characteristics are used. It is recommended that, for a given patient, the chosen brand of tolbutamide not be changed without careful evaluation.

Quality Control↗
PubMed1995

Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data.

The kinetics of oxidation of phenytoin and tolbutamide were determined in freshly isolated hepatocytes and hepatic microsomes from male Sprague-Dawley rats. Similar enzyme kinetic models are applicable to the data from both in vitro systems; a two-site model for phenytoin with a high affinity (Km = 1-5 microM, based on unbound drug concentration), low capacity site and a low affinity, high capacity site, and a one-site model for tolbutamide. Steady-state infusion studies were performed to characterize the Michaelis-Menten parameters for phenytoin disposition in vivo, these data could also be described by a two-site metabolism model (Km 1.3 microM, intrinsic clearance 62 ml/min for unbound drug for the high affinity site). Comparison of in vivo and in vitro parameters (after scaling the latter parameters for either hepatocyte yield or microsomal recovery) showed excellent prediction of in vivo clearance of unbound drug from hepatocyte data (55 ml/min) but underprediction from microsomal data (17 ml/min). In contrast to phenytoin, the in vivo clearance of tolbutamide (1.5 ml/min for unbound drug) was equally well predicted by both hepatocyte (2.4 ml/min) and microsomal (3.1 ml/min) studies. The difference between the utility of in vitro systems to predict the in vivo clearance of these two drugs, which show similar pharmacrokinetic properties (low clearance restricted to unbound drug concentration in blood), may be a consequence of the particular terminal metabolite formed in each in vitro system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Interaction of pargyline with tolbutamide in rabbits.

Acute treatment of rabbits with pargyline (50 mg/kg, ip, 30 min before tolbutamide) significantly increased the elimination half life and AUC0-->infinity of tolbutamide resulting in prolonged hypoglycaemia. Similar treatment also prolonged the half life of antipyrine which is used as model drug to indicate hepatic microsomal enzyme activity in vivo confirming that pargyline treatment delayed the elimination of tolbutamide in rabbits by inhibiting its hepatic metabolism.

Animals↗
PubMed1976

[Non-saturable cooperative binding of tolbutamide to rat endocrine pancreas. Criteria of specificity].

The binding of 3H-tolbutamide to isolated islets, which shows a cooperative non-saturable pattern up to about 5 X 10(-5) M, was confirmed. Binding to exocrine pancreatic tissue shows much less cooperativity. Among congeners of tolbutamide, unlabelled carbutamide and chlorpropamide in isodynamic concentrations, as well as diazoxide in an exactly antagonistic amount, behave like tolbutamide 5 X 10(-5) M itselt by cancelling cooperativity when added to the labelled drug. Glipizide and glibenclamide do not.

Animals↗
PubMed1977

Interaction of tolbutamide and chloramphenicol in diabetic patients.

In study 1 we investigated 8 diabetic female patients treated with tolbutamide who received chloramphenicol to combat urinary tract infections. In 5 patients, chloramphenicol was found to produce a distinct decrease of glycemia. Evaluation of the whole series revealed that the latter averaged 31.5%. No patient developed a marked hypoglycemia. With one exception, the values of immunoreactive insulin (IRI) in serum were within normal. In study 2 we investigated another series of 8 diabetic patients. Given chloramphenicol, 7 patients registered an almost twofold increase in the mean morning tolbutamide level in serum and glycemia decreased by one fourth. No patient developed severe hypoglycemia. Tolbutamide increase in serum was not associated with a rise of IRI level in serum. All patients displayed steady chloramphenicol level in serum. Potential reasons for the development of hypoglycemia during the treatment with sulphonylurea antidiabetics are discussed.

Aged↗
PubMed1963

EFFECT OF TOLBUTAMIDE ON WEIGHT GAIN, BLOOD SUGAR AND SERUM PROTEINS IN GERIATRIC PATIENTS.

Insulin has been used in the past to stimulate appetite and in the treatment of malnutrition. Because of the hypoglycemic property of tolbutamide, the effect of this drug on the induction of weight gain was evaluated. Statistical analysis of the results of a double-blind study on 18 geriatric patients who ingested tolbutamide, 1000 mg. before breakfast and 1000 mg. before lunch, revealed no effect on body weight, the fasting blood sugar level, or the total and fractionated serum protein values.

Blood Glucose↗
PubMed1963

CLINICAL STUDIES OF TOLAZAMIDE AND TOLBUTAMIDE: COMPARATIVE EFFECTIVENESS OF CONTROL OF DIABETES MELLITUS.

Tolazamide, a new oral hypoglycemic agent, was compared with tolbutamide, a related chemical compound, for stability of control of 12 patients suffering from maturity-onset diabetes mellitus. A short 12-week study was conducted which incorporated a cross-over design and the results were examined by variance analysis after dosage was individualized to the patient's requirements. Greater stability of fasting blood sugar was found on tolazamide; patients also had less glycosuria and lower fasting blood sugar on tolazamide. Tolazamide appeared to be between five and six times as potent as tolbutamide, mg. for mg.No hepatic, renal, hematologic or symptomatic toxic reactions were observed during the total of 72 person-weeks of tolazamide therapy.

Biomedical Research↗
PubMed1977

Determination of phenylbutazone, tolbutamide and metabolites in plasma and urine using chemical ionization mass spectrometry.

Quantitative analytical procedures for the analysis of phenylbutazone and tolbutamide levels in plasma have been developed which involve the addition of deuterium labeled internal standards to plasma followed by extraction and direct sample insertion into a mass spectrometer operating under chemical ionization conditions. Peak height ratios used to calculate plasma levels were determined by using either selected ion monitoring or repetitive scan data. The scan approach was used in a related procedure for the simultaneous determination of tolbutamide and two metabolites from urine. The accuracy, precision and sensitivity of the direct sample insertion approach to drug level measurement has been determined. Examples are given of data obtained in the course of pharmacokinetic studies in which this analytical approach appears to offer advantages in the analysis of multicomponent mixtures encountered in drug-drug interaction studies.

Animals↗
PubMed1975

Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and warfarin metabolism.

The influence of sulfamethizole on the metabolism of diphenylhydatoin (DPH) tolbutamide, and warefarian is examined. In 8 patients DPH means half-life (T/2) increased from 11.8 plus or minus 3.6 hr to 19.6 plus or minus 5.2 hr and mean metabolic clearance rate (MCR) decreased from 43.7 plus or minus 16,8 to 28.1 plus or minus 9.1 ml/min durus or minus 1.2 to 9.2 plus or minus 1.2 hr MCR decrease from 17.0 plus or minus 5.4 to 10.5 plus or minus 1.2 ml/min. In 2 patients warfarin T/2 increased fron an average of 64.7 to 92.7 hr and MCR decreased from 1.65 ml/min to 1.05 ml/min. In 4 patients on long-term DPH treatment after 1 wk on sulfamethizole inhibits hepatic metabolism of DPH, tolbutamide, and warfarin.

Depression, Chemical↗
PubMed1979

Spectrophotometric determination of tolbutamide, thiamine hydrochloride, and pyridoxine hydrochloride in combination products.

The first derivative curve is used for tolbutamide determination in unit-dose tablets and in combination products. The absorbance contribution from tablet excipient and coexisting components, thiamine and pyridoxine, is thereby nullified. The interference from tolbutamide during thiamine and pyridoxine determination is eliminated by solvent extraction and pH-induced differential spectrophotometry. Thiamine is measured at the isosbestic point of pyridoxine. The latter is determined by the differential absorbance measurement at two wavelengths with the consequent computation of the delta absorbance value.

Drug Combinations↗