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PubMed1988

Lack of efficacy of cimetidine and ranitidine as inhibitors of tolbutamide metabolism.

We investigated the effect of 4 days pretreatment with cimetidine (1.2 g daily) and ranitidine (0.3 g daily) on tolbutamide disposition in an open randomised, cross-over study design involving 8 healthy adult male volunteers. Control half-life of tolbutamide 6.29 h was not significantly altered by cimetidine (6.93 h) or ranitidine (6.97 h). The corresponding apparent oral clearance (ml.min-1.kg-1) were not significantly different: 0.26 (control), 0.24 (cimetidine) and 0.25 (ranitidine). Apparent volume of distribution was also unaltered 0.140 l.kg-1 (control), 0.141 l.kg-1 (cimetidine) and 0.146 l.kg-1 (ranitidine). It is suggested that the hepatic monooxygenase isozyme that catalyses the rate-limiting conversion of tolbutamide to its hydroxy derivative is not susceptible to the inhibitory effect of cimetidine or ranitidine.

Adult↗
PubMed1975

Interaction of diphenylhydantoin (DPH) and tolbutamide in man.

The influence of tolbutamide administration on the plasma concentrations of diphenylhydantoin (DPH) was investigated in seventeen long-stay patients with epilepsy. Tolbutamide, 0.5 g 2-3x daily, considerably increased the proportion of non-protein-bound DPH in plasma (mean: 44.6% of control values). The increase was transient, unlike the decrease found in total plasma DPH-concentration (approx. 10% of control values). In vitro experiments confirmed that the interaction between DPH and tolbutamide was due to displacement of DPH from plasma proteins. Some factors that limit the capacity to metabolise DPH in the liver are discussed; they may increase the risk of DPH-intoxication in patients who take sulphonyl-ureas.

Adult↗
PubMedDate not supplied

Insulinopenia in impaired glucose tolerance preservation of insulin response to I.V. arginine and tolbutamide.

Immunoreactive insulin (IRI) response to successive i.v. injections of glucose (0.3 g/kg), arginine (5 g) and tolbutamide (20 mg/kg) was measured in 11 non-obese patients with mild glucose intolerance and 11 control subjects. In 3 of the patients the IRI response to i.v. arginine and subsequent i.v. glucose was also measured. The mean peak IRI level following glucose was grossly diminished in the patients compared to controls but peak IRI levels following arginine and tolbutamide were similar in the two groups. Administering arginine prior to glucose in the 3 patients tested resulted in a lowering of the IRI response to arginine but no increase in the IRI response to glucose. The decreased IRI response to i.v. glucose associated with an adequate response to i.v. arginine and tolbutamide in these patients suggests a failure of the B-cell sensor mechanism for glucose and may provide a physiological explanation for the recognized value of restricting carbohydrate relative to protein in the treatment of this condition. Any defect in the sensor mechanism for arginine appears quantitatively much less severe than that to glucose.

Adult↗
PubMedDate not supplied

In vitro effect of exogenous insulin on insulin secretion. Studies with glucose, leucine, arginine, aminophylline and tolbutamide.

Using rat pancreatic islets and the perfused rat pancreas, the effect of exogenous insulin on insulin secretion mediated by glucose, leucine, arginine, aminophylline and tolbutamide was studied. (1) In both systems the insulin releasing capacity of glucose was inhibited by exogenous insulin. In the perfused pancreas the inhibition concerned the first and the second phase of insulin release; (2) the EC50 (half-maximal inhibitory effect of insulin on glucose-induced insulin secretion) in islets was 1.2 nM (= 160 microU/ml) and 2.8 nM (390 microU/ml) in perfused pancreas; (3) exogenous insulin also inhibited insulin release in response to leucine and arginine in the isolated islet system and in the perfused pancreas; (4) using aminophylline and tolbutamide in combination with glucose, the extent of the inhibitory effect of insulin was in the range of the inhibitory effect when glucose was used alone as stimulator in islets. Data suggest that the insulinogenic action of physiological stimulators including glucose, leucine and arginine is inhibited by exogenous insulin whereas this seems not to be the case when insulin release was stimulated by aminophylline and tolbutamide. Comparing the EC50s, isolated islets seem to be more sensitive to inhibition than the perfused pancreas when glucose was used as stimulator. As far as glucose is concerned the inhibitory effect seems to depend on the extent of its concentration and/or the extent to which the mechanism of insulin release is sensitive to stimulation. The EC50 of the inhibitory effect of exogenous insulin was in the range of dissociation constant of binding of insulin to insulin receptors of islets.

Aminophylline↗
PubMed1997

Glucose tolerance and mortality, including a substudy of tolbutamide treatment.

Mortality according to glucose tolerance was studied to determine the prognosis of impaired glucose tolerance. Among 2500 persons tested in a community screening programme in 1962-1965 and followed-up for mortality to the end of 1987, age-sex-adjusted mortality rates were 37.9 +/- 1.9, 53.6 +/- 4.2, and 70.1 +/- 3.6 deaths per 1000 person-years (+/-SE) in those with normal glucose tolerance, impaired glucose tolerance, and diabetes by World Health Organization criteria at baseline. Age-sex-adjusted mortality rates due to ischaemic heart disease were 14.3 +/- 1.1, 16.3 +/- 2.4, and 25.8 +/- 2.0 deaths per 1000 person-years, respectively. Using criteria predating those of the World Health Organization 147 men with abnormal glucose tolerance were entered into a randomized clinical trial in which 49 were treated with tolbutamide for approximately 10 years. Those treated had lower mortality rates from all causes (mortality rate ratio = 0.66, 95% confidence interval = 0.39, 1.10) and from ischaemic heart disease (mortality rate ratio = 0.42, 95% confidence interval = 0.16, 1.12) than those not receiving tolbutamide. Thus mortality rates are increased in persons with impaired glucose tolerance and diabetes, and the small clinical trial suggests that tolbutamide may be beneficial in men with abnormal glucose tolerance.

Adolescent↗
PubMed1998

Tolbutamide blocks postsynaptic but not presynaptic effects of adenosine on hippocampal CA1 neurones.

Extracellular recording in the CA1 pyramidal cell layer of rat hippocampal slices was used to examine the effect of the ATP-sensitive potassium channel blocker tolbutamide and the channel opener levcromakalim on responses to adenosine. Tolbutamide 1 mM blocked the inhibitory effect of adenosine on the size of orthodromic population spikes but had no effect on the inhibitory action of adenosine on field EPSPs. Tolbutamide also blocked the suppression by adenosine of repetitive antidromic spikes induced in calcium-free media with high magnesium but did not prevent the effects of baclofen. Levcromakalim 100 microM potentiated inhibitory effect of adenosine, but not baclofen, on orthodromic population spikes. The results show that at postsynaptic, but not presynaptic, sites adenosine may activate an ATP-sensitive potassium channel.

Adenosine↗
PubMed1975

Inotropic effects of tolbutamide in man.

The hemodynamic responses of normal subjects to intravenous injections of tolbutamide, 250 mg., and 1,000 mg., were assessed by measurements of serial systolic time intervals. Analysis of results, compared to saline control, revealed evidence of minor inotropic effects during the period five to 10 minutes after infusion. Small but statistically significant (p less than 0.05) decreases in pre-ejection phase and electromechanical systole were noted. The time response of these changes did not correlate with dose of blood level of tolbutamide, and appeared to coincide with peak insulin levels. No inotropic or chronotropic effects were seen during the first four minutes after infusion, suggesting that the myocardial adenyl cyclase-stimulating properties of the drug, previously demonstrated in vitro, are not significant in intact man. The minor late inotropic effects are of doubtful clinical significance, and cannot be invoked to explain the reported increased cardiovascular mortality of patients treated with tolbutamide.

Adult↗
PubMed1989

Effects of tolbutamide, glibenclamide and diazoxide upon action potentials recorded from rat ventricular muscle.

Drugs which influence the electrical activity of insulin-secreting B cells of mammalian islets of Langerhans by closing (tolbutamide and glibenclamide) or opening (diazoxide) ATP-sensitive potassium channels were applied to the ventricular muscle of the rat. Action potentials were recorded from ventricular epicardium of perfused intact rat hearts. Tolbutamide (0.5-2.0 mM), glibenclamide (0.01-0.1 mM) and diazoxide (0.5 mM) each evoked a dose-dependent increase (7-33%) in the duration of the ventricular action potential measured at 50% of repolarization. These drugs were without effect upon the resting membrane potential or the peak of the action potential. Single-channel recordings of ATP-sensitive K+ channels were obtained from excised membrane patches of enzymatically isolated rat ventricular myocytes. Tolbutamide and diazoxide inhibited openings of ATP-sensitive K+ channels. Diazoxide inhibited ATP-sensitive K+ channel openings in the presence of ATP. Diazoxide did not evoke opening of ATP-sensitive K+ channels. It is concluded that these drugs could act to increase the duration of the cardiac action potential by inhibiting openings of ATP-sensitive K+ channels.

Action Potentials↗
PubMed1985

Effects of tolbutamide on blood flow in islets and exocrine tissue of the rat pancreas.

The influence of tolbutamide (20 mg/kg and 100 mg/kg i.v.) on blood flow to the entire pancreatic gland and to its endocrine tissue was studied in anaesthetized rats. Non-radioactive microspheres 8.8 micron diameter were used for determination of local blood flow rates. The islet tissue was subsequently stained intravitally with dithizone. The organ was subdivided into small samples, frozen and thawed then scanned in the microscope for spheres in endocrine and exocrine tissue, respectively. Tolbutamide only insignificantly affected total organ blood flow (0.53 ml X min-1 X g-1, controls; 0.61 ml X min-1 X g-1 lower dose; 0.39 ml X min-1 X g-1 higher dose) but significantly increased the percent islet perfusion (3.0% controls; 6.6% lower dose; 10.5% higher dose of tolbutamide). The results favour the view that these vascular effects might facilitate insulin release into the systemic circulation.

Animals↗
PubMed1987

Comparative diagnostic value of the calcium-pentagastrin test versus the tolbutamide test in a patient with a somatostatinoma.

We describe a patient with a small somatostatinoma of the papilla of Vater without clinical evidence for diabetes mellitus, diarrhea, steatorrhea, or cholelithiasis, showing normal plasma basal levels for somatostatinlike immunoreactivity. The diagnosis was based on histologic and immunohistochemical analysis of tumor tissue and hypersomatostatinemia induced by the calcium-pentagastrin test. Before removal of the tumor both diagnostic tests recommended for the detection of a somatostatinoma, a tolbutamide test and a calcium-pentagastrin test, were performed. Whereas the calcium-pentagastrin test provoked a markedly elevated plasma somatostatin level in association with a depressed plasma neurotensin level, the tolbutamide test surprisingly did not. After removal of the tumor the calcium-pentagastrin test no longer induced hypersomatostatinemia. Further studies are needed to determine whether the calcium-pentagastrin test is a more reliable diagnostic test than the tolbutamide test in somatostatinomas with normal plasma basal levels.

Adenoma, Islet Cell↗
PubMed1975

Effects of insulin, tolbutamide, and glucagon on activities of jejunal carbohydrate-metabolizing enzymes in humans.

The activities of jejunal carbohydrate-metabolizing enzymes show adaptive drugs, and sex hormones. To learn whether insulin, tolbutamide, and glucagon had effects on these enzymes, we performed serial peroral jejunal biopsies in normal young men and in obese patients, before and after treatment with these agents. Jejunal mucosa was assayed for glycolytic enzyme activities, pyruvate kinase (PK), hexokinase (HK), and fructose-1,6-diphosphate aldolase (FDPA), and the nonglycolytic enzyme activity, fructose diphosphatase (FDPase). Insulin significantly increased the activity of jejunal PK (+48% change from control) and HK (+6%), decreased the activity of FDPase (-36%),and had no effect on FDPA. Glucagon had opposite effects; the activity of PK was decreased (-33%) and FDPase was increased (+50%). Tolbutamide significantly increased the activities of PK (+47%), HK (+14%), and FDPA (+7%), and decreased the activities of FDPase (-36%). The results of tolbutamide on glycolytic enzyme activities were independent of endogenous insulin. The data support the concept that jejunal carbohydrate-metabolizing enzymes in man respond to hormones and drugs similar to responses observed in rat liver. This is important because it now gives us a means of studying the actions of these hormones directly in human tissue.

Adolescent↗
PubMedDate not supplied

Insulin release from pancreatic islets of fetal rats mediated by leucine b-BCH, tolbutamide, glibenclamide, arginine, potassium chloride, and theophylline does not require stimulation of Ca2+ net uptake.

In pancreatic islets of fetal rats the effect of glucose (3 and 16.7 mM), glyceraldehyde (10 mM), leucine (20 mM), b-BCH (20 mM), tolbutamide (100 micrograms/ml), glibenclamide (0.5 and 5.0 micrograms/ml) arginine (20 mM), KCl (20 mM) and theophylline (2.5 mM) on 45Ca2+ net uptake and secretion of insulin was studied. All compounds tested failed to stimulate 45Ca2+ net uptake. However, in contrast to glucose and glyceraldehyde, leucine, b-BCH, tolbutamide, glibenclamide, arginine, KCl and theophylline significantly stimulated release of insulin. This effect could not be inhibited by the calcium antagonist verapamil (20 microM). Elevation of the glucose concentration from 3 to 5.6 mM did not alter 86Rb+ efflux of fetal rat islets but inhibited 86Rb+ efflux of adult rat islets. Stimulation of 86Rb+ efflux with tolbutamide (100 micrograms/ml), leucine (20 mM) or b-BCH (20 mM) in the presence of 3 mM glucose was also ineffective in fetal rat islets. Our data suggest that stimulation of calcium uptake via the voltage dependent calcium channel is not possible in the fetal state. They also provide evidence that stimulators of insulin release which are thought not to act through their metabolism, initiate insulin secretion from fetal islets by a mechanism which is different from stimulation of calcium influx.

Amino Acids↗
PubMed1991

Heterogeneous changes in [Ca2+]i induced by glucose, tolbutamide and K+ in single rat pancreatic B cells.

The effects of glucose, tolbutamide and K+ on cytosolic free Ca2+ ([Ca2+]i) in single rat pancreatic B cells were examined using Fura-2 and dual wavelength microfluorimetry. At basal glucose concentration (2.8 mM), about half of the cells were found to display spontaneous Ca2+ oscillations. Glucose (greater than or equal to 11.1 mM), tolbutamide (greater than or equal to 50 microM) and K+ (50 mM) induced rises in [Ca2+]i that could be inhibited by the Ca2+ channel blocker D600. The pattern of response and the sensitivity to the secretagogues were characterized by a marked heterogeneity. The majority of the cells responded to glucose and tolbutamide by a progressive increase in [Ca2+]i onto which sinusoidal oscillations were superimposed. The periodicity of these oscillations was about 2.5/min. Occasionally, some cells displayed slow and major waves in Ca2+ levels (about 0.2/min). None of the cells responded to glucose by displaying an initial decrease in [Ca2+]i. Likewise, the sugar failed to decrease [Ca2+]i in the absence of extracellular Ca2+. The present study shows that, despite a large heterogeneity of the response, the majority of the pancreatic B cells respond to different secretagogues by displaying fast [Ca2+]i oscillations that are reminiscent of the bursts of electrical activity recorded in B cells.

Animals↗
PubMed1982

Glucagon and tolbutamide as insulin secretagogues in the pig (Sus domesticus).

1. Glucagon tolbutamide, either alone or in combination, were injected i.v. into pigs and the effect upon plasma glucose and insulin concentrations measured. 2. Glucagon gave similar insulin responses to those seen in humans, but insulin responses to tolbutamide were less than in humans. 3. Combined doses of glucagon and tolbutamide gave similar, though reduced, responses to those seen in humans. At the highest combined doses applied, glucose concentration remained reduced for up to 6 hr. The insulin responses were approximately equal to the sum of the responses to each substance given alone.

Animals↗
PubMed1981

Comparative study on the effects of a hypoglycemic 2-substituted-2-imidazoline derivative (DG-5128) and tolbutamide on insulin secretion from and insulin synthesis in the isolated rat pancreatic islets.

2[2-(4,5-Dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate (DG-5128) was found to stimulate the glucose-primed insulin secretion from the isolated rat pancreatic islets throughout the incubation period, unlike tolbutamide which stimulated it only in the initial phase of incubation. The effect of DG-5128 was more pronounced at a higher glucose concentration (5 mg/ml). In the islet perifusion study, DG-5128 was also found to stimulate the glucose-induced insulin secretion in both the first and the second phases of the reaction, in contrast to tolbutamide which stimulated only the first phase of insulin secretion from the perifused islets. DG-5128 gave no significant effect on the glucose-stimulated increase in incorporation of [3H]leucine into the proinsulin and insulin fractions, while tolbutamide significantly inhibited the incorporation especially at a low glucose concentration (1 mg/ml). These and the previous findings indicate that DG-5128 is a new class of hypoglycemic agent with a unique mode of action different from the known hypoglycemics ever reported.

Animals↗
PubMed2005

Changes in muscle mRNAs for hexokinase, phosphofructokinase-1 and glycogen synthase in acute and persistent hypoglycemia induced by tolbutamide in chickens.

To elucidate the specificity of glucose metabolism in chicken skeletal muscle, changes in mRNA levels of hexokinase I (HKI), hexokinase II (HKII), phosphofructokinase-1 (PFK-1) and glycogen synthase (GS) were characterized in acute and persistent hypoglycemia induced by tolbutamide administration. In acute hypoglycemia, induced by a single dose of tolbutamide (100 mg/kg body mass), HKII, PFK-1 and GS mRNA levels remained unchanged; however, levels of HKI mRNA and glucose transporter 1 (GLUT1) were significantly increased 4 h after administration. In persistent hypoglycemia, induced by sequential administration of tolbutamide (100 mg/kg body mass) 3 times a day for 5 days, GS mRNA was significantly increased at day 5, while HKI, HKII and PFK-1 mRNA levels remained unchanged. These results suggest that HKI is responsible for glucose transport into skeletal muscle in acute hypoglycemia and that glucose preferentially enters the glycogenic pathway before the glycolytic pathway in persistently hypoglycemic chickens.

Amino Acid Sequence↗
PubMed2004

Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of K(ATP) channel components.

Clonal insulin-secreting BRIN-BD11 cells were used to examine effects of chronic 72-144 h exposure to the sulphonylureas tolbutamide and glibenclamide on insulin release, cellular insulin content, and mRNA levels of the Kir6.2 and SUR1 subunits of the beta-cell K(ATP) channel. Chronic exposure for 72-144 h to 5-100 microM tolbutamide and glibenclamide resulted in a time- and concentration-dependent irreversible decline in sulphonylurea-induced insulin secretion. In contrast, the decline in cellular insulin content induced by chronic exposure to high concentrations of sulphonylureas was readily reversible. Chronic exposure to tolbutamide or glibenclamide had no effect upon transcription of the Kir6.2 or SUR1 subunits of the pancreatic beta-cell K(ATP) channel. Whilst further studies are required to understand the precise nature of the chronic interactions of sulphonylurea with the insulin exocytotic mechanism, these observations may partially explain the well-known progressive failure of sulphonylurea therapy in type 2 diabetes.

ATP-Binding Cassette Transporters↗
PubMed2001

Effects of tolbutamide and N-benzoyl-D-phenylalanine (NBDP) on the regulation of [Ca2+]i oscillations in mouse pancreatic islets.

The sulfonylurea derivative, tolbutamide, and the phenylalanine derivative, N-benzoyl-D-phenylalanine (NBDP), both of which stimulate insulin secretion through interaction with the sulfonylurea receptor (SUR1), were studied for their ability to increase the [Ca(2+)](i) and to interact with the glucose-induced slow large amplitude [Ca(2+)](i) oscillations in isolated mouse pancreatic islets. Tolbutamide as well as NBDP induced [Ca(2+)](i) oscillations of extremely slow frequency. Both compounds also lowered the threshold for the glucose-induced slow large amplitude [Ca(2+)](i) oscillations and significantly reduced their frequency in intact islets as well as in single pancreatic beta cells. These [Ca(2+)](i) oscillations apparently require a glucokinase-mediated glycolytic flux. This conclusion is supported by the observations that KIC, a mitochondrial fuel, cannot replace glucose in this synergism and that mannoheptulose, an inhibitor of glucokinase and glucose-induced insulin secretion, abolishes these slow [Ca(2+)](i) oscillations. In conclusion, these compounds potentiate the effect of glucose. This additive effect is the likely result of a synergistic closing action upon the ATP-sensitive K(+) (K(ATP)) channel, mediated in the case of glucose through an action upon the channel protein itself of ATP generated in glucose catabolism and in the case of tolbutamide and NBDP upon the sulfonylurea receptor (SUR1) associated with this channel.

Animals↗