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PubMed2000

Effect of clarithromycin on the pharmacokinetics of tolbutamide.

The aim of this 2 x 2 randomized double blind crossover study was to evaluate the effect of a single dose of clarithromycin on the pharmacokinetics of tolbutamide in nine healthy male volunteers. Each volunteer received orally 500 mg of tolbutamide, or 500 mg of tolbutamide and 250 mg of clarithromycin. The washout period between the two treatments was 7 days. Serum levels of tolbutamide were determined by HPLC. Serum profiles were analysed using a non-compartmental model. Blood glucose levels were also estimated using a glucometer (Ames) and Glucostix (Bayer). There was approximately 20% increase in mean absorption rate constant and 26% increase in mean bioavailability of tolbutamide in the presence of clarithromycin. A hypoglycemic effect was reported upon co-administration of the two drugs.

Adult↗
PubMed1982

Therapeutic effect of tolbutamide in non-insulin dependent diabetes mellitus (NIDDM). Relation to beta-cell function.

The therapeutic effect of tolbutamide (1.5 g daily) in a random sample of patients with non-insulin dependent diabetes mellitus (NIDDM), was studied in a controlled, double-blind cross-over trial of 13 women and 6 men, aged 40-65 years and of 85-155% ideal body weight. The trial comprised C-peptide determinations during a standard carbohydrate rich meal followed by four periods of 3 months in which alternating tolbutamide and placebo were given. From the beginning to the end of the treatment periods fasting blood glucose was reduced from 11.9 +/- 1.1 (mean +/- SEM) to 10.0 +/- 0.8 mmol/l (P less than 0.025), glycohaemoglobin from 12.8% +/- 0.7 to 11.3% +/- 0.5 (P less than 0.02) with a close correlation between fasting blood glucose and glycohaemoglobin (r = 0.87, P less than 0.001). The observations during the first 3 months of study was not included in the calculations. Fasting C-peptide and fasting insulin concentrations were not significantly altered by tolbutamide treatment. The effect of tolbutamide was inversely correlated to the C-peptide response to the standard test meal at the start of the trial (r = 0.76, P less than 0.01), so that patients with the most pronounced beta-cell failure had the greatest therapeutical effect. The beta-cell response to the test meal could not identify patients, whose fasting blood glucose would be normalized by tolbutamide treatment.

Adult↗
PubMed1979

Effect of tolbutamide on plasma catecholamine in insulin dependent diabetics.

In 4 cases of insulin dependent diabetics, blood levels of glucose, C-peptide reactivity (CPR), free fatty acid, and catecholamines were followed after the intravenous tolbutamide response test. Plasma CPR was low and did not respond to tolbutamide injection, and blood levels of glucose and free fatty acid did not change during the test. Fifteen min after the tolbutamide injection, plasma epinephrine plus norepinephrine and norepinephrine levels fell to 87.5% and 67.4% of the initial values, respectively. These results suggest that decrease in the blood glucose and free fatty acid levels usually observed after tolbutamide injection is not the direct action of drug, but is secondary to insulin secretion, and tolbutamide-induced decrease in catecholamines may contribute to the secretion of insulin from the pancreatic beta-cells.

Catecholamines↗
PubMed1982

Tolbutamide stimulates gastric somatostatin release from isolated perfused rat stomach.

The effect of tolbutamide on somatostatin release from the isolated perfused stomach was investigated in both normal and streptozotocin-diabetic rats. Tolbutamide (10, 100, and 1000 microgram/ml) evoked a significant and dose-dependent increase in gastric somatostatin release. The tolbutamide (100 microgram/ml)-induced gastric somatostatin secretion was not influenced by differences in glucose concentration (1.5, 5.5, and 16.5 mM) throughout the perfusion period. Tolbutamide (100 microgram/ml)-induced gastric somatostatin release in streptozotocin-diabetic rats was significantly higher than in normal rats. Thus, tolbutamide is a potent secretagogue for gastric somatostatin secretion, and this effect is more prominent in diabetic animals.

Animals↗
PubMed1986

Differential activities of tolbutamide, tolazamide, and glyburide in vitro on rabbit myocardial membrane Ca2+-transporting ATPase activity.

At clinically achievable concentrations (10(-9) to 5 X 10(-6) M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea IC50, 10(-7) M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported; in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 X 10(-6) M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5-40 ng/micrograms membrane protein) to myocardial membranes incubated with 10(-7) M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme. Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.

Animals↗
PubMed1991

Effect of linogliride on hormone release from perfused rat pancreas. Fuel dependence and desensitization by tolbutamide.

We examined the effect of the hypoglycemic drug linogliride on hormone release from the in vitro perfused rat pancreas. Linogliride stimulated insulin release in the absence of glucose either in the presence or absence of a physiological mixture of amino acids. In addition, linogliride inhibited amino acid-induced glucagon release. Half-maximal effects of linogliride on insulin and glucagon release were achieved at concentrations as low as 26 and 3 microM, respectively. The effects of linogliride on hormone release largely resembled those of tolbutamide. In the absence of amino acids, the stimulation of insulin release by linogliride or tolbutamide was transient. When the pancreas had been preperfused for 20 min with tolbutamide, linogliride no longer had an effect on hormone release. Likewise, tolbutamide remained without effect in pancreases preperfused with linogliride. These data suggest that linogliride and tolbutamide may have a similar mechanism of action.

Amino Acids↗
PubMed1992

Tolbutamide inhibits cAMP-dependent phosphorylation of liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

The activity of a bifunctional enzyme, liver 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase (F-2,6-Pase), which regulates the level of liver fructose-2,6-bisphosphate (F-2,6-P2), the most potent activator of PFK, is modulated by its phosphorylation rate mainly catalyzed by cAMP-dependent protein kinase A (PKA). To elucidate the action mechanism of sulfonylurea on liver F-2,6-P2 production, effects of tolbutamide on PKA-dependent phosphorylation of purified liver PFK-2/F-2,6-Phase protein and on kinase and phosphatase activities of the purified enzyme were examined in vitro. The purified enzyme was phosphorylated in the presence of the catalytic subunit of PKA, and tolbutamide inhibited the enzyme phosphorylation catalyzed by PKA in a dose-dependent manner. By adding the same dosages of tolbutamide used in the phosphorylation experiment, reduced activity of PFK-2 and increased activity of F-2,6-Pase in the presence of PKA were restored to the levels observed in the absence of PKA. On the other hand, carboxytolbutamide, an inactive metabolite of tolbutamide, had little effect on enzyme phosphorylation and activity. Our results indicate that tolbutamide inhibits a phosphorylation of the liver PFK-2/F-2,6-Pase catalyzed by PKA along with an activation of PFK-2 and an inactivation of F-2,6-Pase, leading to liver F-2,6-P2 production.

Animals↗
PubMed1996

cAMP-signaling pathway acts in selective synergism with glucose or tolbutamide to increase cytosolic Ca2+ in rat pancreatic beta-cells.

cAMP and the insulinotropic peptides that raise cAMP glucose-dependently increase the cytosolic free Ca2+ concentration ([Ca2+]i) in pancreatic beta-cells, which is tightly linked to the potentiation of glucose-induced insulin release. We examined whether cAMP increases [Ca2+]i in specific cooperation only with glucose or also with other insulin secretagogues that act through different mechanisms. [Ca2+]i in single rat pancreatic beta-cells was measured by dual-wavelength fura-2 microfluorometry. In the presence of a stimulatory concentration of glucose (8.3 mmol/l) and the moderate elevation in [Ca2+]i induced by it, forskolin, an activator of adenylyl cyclase, or dibutyryl cAMP produced a marked additional increase in [Ca2+]i but was ineffective at the basal 2.8 mmol/l glucose. These cAMP-elevating agents also potentiated the effect of tolbutamide on [Ca2+]i. The cAMP-induced increase in [Ca2+]i was completely and selectively inhibited by a blocker of cAMP-dependent protein kinase A (PKA), and by nitrendipine, a blocker of the L-type Ca2+ channel. However, in the presence of high KCl and the [Ca2+]i elevation induced by it, a rise in cAMP failed to further increase [Ca2+]i, whereas BAY K8644, an agonist of L-type Ca2+ channels, evoked an additional increase in [Ca2+]i. Under low Na+ conditions, the [Ca2+]i response to cAMP was observed in the majority of the cells. In the cells in which glucose at 4.5-5 mmol/l was inadequate to increase [Ca2+]i, the glucose together with a rise in cAMP often increased [Ca2+]i. Likewise, tolbutamide and a rise in cAMP acted in concert to increase [Ca2+]i. Thus, cAMP left-shifted the concentration-[Ca2+]i response relationship for glucose and tolbutamide. In conclusion, the cAMP-PKA pathway acts in selective synergism with glucose and tolbutamide to initiate [Ca2+]i signals in pancreatic beta- cells. cAMP appears to regulate beta-cell sensitivity to glucose and tolbutamide. In contrast, cAMP fails to cooperate with high KCl to increase [Ca2+]i. It is suggested that cAMP acts mainly on a site that is more proximal but functionally linked to the L-type Ca2+ channel, thereby finally increasing Ca2+ influx through this channel.

Animals↗
PubMed1986

The response of a non-functional VIP- and somatostatin-containing tumour to tolbutamide in vitro.

A patient with a tumour containing clinically non-expressive somatostatin (SRIF) and vasoactive intestinal peptide (VIP) was studied in vivo with basal and tolbutamide-provoked SRIF and VIP measurements and failed to respond to tolbutamide infusion. An acute cell dispersion model was used to study this tumour after resection. Incubation of tumour cells in tolbutamide (2 mg/ml) resulted in increases in intracellular SRIF but not in the levels of SRIF released into the incubating medium. In contrast, incubation of tumour cells with tolbutamide decreased supernatant (extracellular) and total (intracellular) VIP by 50%, suggesting a local peptide-peptide modulation of VIP release by high intracellular levels of SRIF or, alternatively, suppression of VIP synthesis and/or release by tolbutamide. Failure of 'nonfunctional' tumours to produce symptoms or abnormal plasma peptide levels may be due to defects in peptide release or complex paracrine peptide-peptide interactions.

Aged↗
PubMed1976

Influence of diftalone on tolbutamide test and i.v. glucose tolerance test.

In 16 healthy volunteers tolbutamide tests or i.v. glucose tolerance tests were performed with and without previous oral administration of 1000 mg diftalone. Blood sugar and serum insulin were assayed in regular intervals. Both with and without previous administration of diftalone blood glucose after tolbutamide did not show any difference. IRI response to tolbutamide, measured by planimetrical integration showed a statistically significant augmentation (0.05 greater than p greater than 0.01) after diftalone. Glucose assimilation (K-value) after diftalone was decreased (0.05 greater than p greater than 0.01) yet within normal range. For the accompanying insulin levels however no statistically significant difference was observed. In addition a normalisation of pathological tolbutamide test after diftalone could be noted in five patients with subclinical diabetes. Our results indicate that diftalone seems to have the following three actions: 1. Enhancement of the tolbutamide action. 2. direct augmentation of IRI secretion, 3. a peripheral action on glucose metabolism.

Adult↗
PubMed1991

[Effect of tolbutamide on lipolytic processes in blood and fat tissue of rats maintained in normothermic and hypothermic conditions].

The effect of tolbutamide administered in vivo or added to the incubation medium on lipolysis in adipose tissue and in blood has been studied in rats. Tissue lipolysis was lowered by 118 to 156% in groups of rats receiving tolbutamide in vivo. The addition of tolbutamide directly to the incubation medium caused an increase in the lipid mobilizing activity, while the addition of insulin inhibited lipolysis in each case. The effect of tolbutamide administered in vivo may be indirect through an increase in insulin binding and/or the drug may influence directly the permeability of cell membrane for ions and glucose. An increase in the lipid mobilizing activity observed in experiments consisting in the addition of tolbutamide to the incubation medium may be linked to the low glucose level and greater demand for free fatty acids or to the low level of insulin in the incubation medium.

Adipose Tissue↗
PubMed2005

[Influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide metabolism using oligonucleotide genotyping microarray].

AIM: To investigate the influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide. METHODS: An oligonucleotide microarray was designed and fabricated to genotype the CYP2C9 accurately and quickly. 137 healthy volunteers were genotyped with the array to investigate the frequency of CYP2C9 functional SNPs. Moreover, 1 homozygous mutant, 9 heterozygous and 10 wild-genotypes subjects in the assay were selected randomly and sequenced directly. After orally taking tolbutamide, blood samples and urine samples were collected, and their pharmacokinetics was studied with HPLC. RESULTS: CYP2C9 *1/*3 were found in 9 of 137 volunteers, CYP2C9 *3/*3 in only one, others were all CYP2C9 *1/*1 wild types. CYP2C9 *2, CYP2C9 *4 and CYP2C9 *5 alleles were not detected. Direct sequencing of the purified PCR products of the heterozygotes, mutant homozygotes and ten wild type individuals gave a corresponding result to that genotyped by microarray. Pharmacokinetic outcome showed that the individuals with CYP2C9 *1/*3 or CYP2C9 *3/*3 had slower metabolic elimination of tolbutamide than those with CYP2C9 *1/*1. CONCLUSION: CYP2C9 genetic polymorphism has a significant influence on the pharmacokinetics of tolbutamide. Pharmacogenomic study will be helpful in guiding rational and individualized medication. Key words: tolbutamide; cytochrom P450 CYP2C9; allele; single nucleotide polymorphism; genotyping

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

Studies on 8-methoxypsoralen tolbutamide interactions in vitro and in vivo.

The present study aimed at characterizing the influence of tolbutamide on the distribution of 8-methoxypsoralen (8-MOP) in mouse serum and organs. Experiments performed in vitro clearly showed that tolbutamide causes competitive displacement of 8-MOP from its binding sites on human serum albumin. Similarly, the amount of labelled compound(s) bound in serum after oral administration of 3H-8-MOP to mice was significantly reduced when tolbutamide was given by the same route. The quantitative distribution of radioactivity from 3H-8-MOP in mouse tissues varied according to organ (liver, intestine, skin, etc.,), and was maximum in the organs of elimination. In all the organs studied, the administration of tolbutamide 2 hours after that of 3H-8-MOP caused a dose-dependent reduction of the radioactive compound(s) present in tissues, suggesting that tolbutamide may accelerate the excretion of 8-MOP and/or its metabolites from the body.

Animals↗
PubMed1988

Inhibition of tolbutamide metabolism by antimalarial drugs.

The effects of mefloquine (MQ), the combination of MQ with sulfadoxine-pyrimethamine (MSP), sulfadoxine (S), pyrimethamine (P) quinine (Q) and quinidine (Qd) on in vitro hepatic metabolism has been studied using tolbutamide as a substrate. The hydroxylation of tolbutamide was determined in the presence of variable concentrations of each compound. Tolbutamide hydroxylase activity in control microsomes was 0.20 +/- 0.13 nmole/min/mg microsomal protein at a substrate concentration of 150 microM. All compounds studied inhibited tolbutamide metabolism as shown by a decrease in 4-hydroxytolbutamide formation. The order of potency of the inhibitors was MSP greater than S greater than MQ greater than Q greater than Qd greater than P. MQ, MSP, S, Q, and Qd were examined in detail for the type of inhibition. MQ and Qd were non-competitive inhibitors, whereas MSP and S were competitive inhibitors and Q was an uncompetitive inhibitor of tolbutamide 4-hydroxylation. These data provide more information on the inhibitory potential of some antimalarial drugs on microsomal enzymes in human liver. S has been shown to be a potent inhibitor in vitro and this finding possibly explains the longer T 1/2 and MRT of MQ when co-administered with S in healthy volunteers. Further studies in man should be attempted in order to understand the clinical relevance of the inhibitory potential of the antimalarial drugs.

Adult↗
PubMed1985

Elevation of the number of cell-surface insulin receptors and the rate of 2-deoxyglucose uptake by exposure of 3T3-L1 adipocytes to tolbutamide.

Sulfonylurea compounds are hypoglycemic agents which by unknown mechanisms alter the amount of insulin receptor and the rate of glucose utilization in tissues exposed to the drugs. In this study the effects on insulin binding and uptake of 2-deoxyglucose by 3T3-L1 adipocytes were assessed after maintaining cell monolayers for 1-3 days in medium containing different concentrations of the sulfonylurea, tolbutamide. The amount of 125I-insulin bound by treated monolayers gradually increased to values 150-250% of those of control monolayers after 2-3 days of exposure to 1.5 mM tolbutamide. Such increases in insulin binding capacity arose primarily from an increase in receptor number and not from an alteration in the affinity of the receptor for insulin. Concomitant with the changes observed for the insulin receptor, tolbutamide-treated monolayers expressed 1.5-2-fold higher rates of uptake of 2-deoxyglucose relative to control monolayers at concentrations of insulin between 0 and 10(-10) M. This study thus demonstrates the responsiveness of adipocytes to tolbutamide and also establishes the usefulness of 3T3-L1 cells as a model system in which to study the mechanism of tolbutamide action, both as it relates to the use of sulfonylurea compounds in clinical applications and as possible probes for perturbing and studying relatively uncharacterized regulatory pathways controlling receptor level and biological responses to insulin.

Adipose Tissue↗
PubMed1984

A probable mechanism for tolbutamide mediated activation of glycogen phosphorylase in the isolated rat heart.

Previous studies have shown that 0.6 mM tolbutamide stimulates the rate of glycogenolysis and transiently increases % phosphorylase a activity in the isolated rat heart. Since tolbutamide has been reported to activate adenylate cyclase, one possible mechanism for the conversion of phosphorylase b to the a form is through a cAMP mediated process. However, we failed to detect any drug-induced changes in tissue cAMP content of rat and rabbit hearts or in basal, Gpp(NH)p stimulated and isoproterenol-stimulated adenylate cyclase activity of sarcolemma prepared from rat, rabbit or dog ventricles. Since tolbutamide can alter calcium transport across cell membranes, we investigated the possibility that the drug's effects on phosphorylase were linked to an elevation in calcium concentration. It was found that tolbutamide was not able to activate phosphorylase when the calcium channel blocker verapamil was present in the perfusate. In addition, the sulfonylurea increased binding of [3H]-verapamil to isolated sarcolemma suggesting that tolbutamide is able to unmask previously inactive calcium channels and thereby stimulate calcium movement into the cell.

Adenylyl Cyclases↗
PubMed2005

Influence of antioxidant (L- ascorbic acid) on tolbutamide induced hypoglycaemia/antihyperglycaemia in normal and diabetic rats.

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia. Increased oxidative stress and decreased antioxidant levels are the leading cause of diabetes and diabetic complications. So it is felt that supplementation of antioxidants may be useful in controlling the glucose levels and to postpone the occurrence of diabetic complications. The objective of our study is to find the influence of antioxidant supplementation (L-ascorbic acid) on tolbutamide activity in normal and diabetic rats. METHODS: L- ascorbic acid/tolbutamide/L-ascorbic acid + tolbutamide were administered orally to 3 different groups of albino rats of either sex in normal and diabetic condition. Blood samples were collected from retro-orbital puncture at different time intervals and were analyzed for blood glucose by GOD-POD method. Diabetes was induced by alloxan 100 mg/kg body weight administered by I.P route. RESULTS: L-ascorbic acid/ tolbutamide produced hypoglycaemic activity in a dose dependant manner in normal and diabetic condition. In the presence of L-ascorbic acid, tolbuatmide produced early onset of action and maintained for longer period compared to tolbutamide matching control. CONCLUSION: Supplementation of antioxidants like L-ascorbic acid was found to improve tolbutamide response in normal and diabetic rats.

Journal Article↗
PubMed1977

Bioassay of tolbutamide for possible carcinogenicity.

A bioassay of tolbutamide for possible carcinogenicity was conducted by administering the test material in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats of each sex were administered tolbutamide at one of two doses, either 12,000 or 24,000 ppm, 5 days a week for 78 weeks, then observed for an additional 28 weeks. Matched-control groups consisted of 15 untreated rats of each sex. All surviving rats were killed at 106 or 107 weeks. Groups of 35 mice of each sex were administered tolbutamide at one of two doses, either 25,000 or 50,000 ppm, 5 days a week for 78 weeks, then observed for an additional 24-26 weeks. Matched-control groups consisted of 15 untreated mice of each sex. All surviving mice were killed at 102-104 weeks. Mean body weights of the treated rats and mice were lower than those of the corresponding matched controls during the entire study; however, survival was not significantly affected by treatment in either species. In both sexes of both species, survival was considered to be adequate for meaningful statistical analyses of the incidence of tumors. In both the rats and the mice, a variety of neoplasms were found in both tolbutamide-treated and control groups. None of the neoplasms were present at a statistically significant increased incidence in treated groups of either species as compared with control groups and were not considered to be compound related. It is concluded that under the conditions of this bioassay, tolbutamide was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

Journal Article↗