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PubMed1975

[Studies on the bio-availability of tolbutamide (author's transl)].

Two different batches of Rastinon 1,0 Hoechst were administered, a year apart, to two groups of healthy subjects (ten and six men, respectively) without any difference in effect on blood sugar being found. The blood sugar concentration was measured in six healthy men before and after oral administration of 1,000 mg tolbutamide (as Rastinon 1,0 Hoechst or tolbutamid tablets Ratiopharm), in a blind test. After tolbutamide Ratiopharm, the area under the blood sugar concentration-time curves was only 29 percent (0-4 hafter medication) and 32 percent (4-8 h after medication) of that after Rastinon 1,0 (P 2alpha less than 0.01), with marked scatter between individuals. Maximal serum concentration was 80 percent below that after Rastinon. The first measurable value was reached 0.8 plus or minus 0.2 h after medication of Rastinon and 3.6 plus or minus 0.8 h after tolbutamide Ratiopharm. The areas under the serum concentration under the curves after tolbutamide Ratiopharm were only 16 percent (0-4 h after medication) and 19 percent (0-8 h after medication) of those after Rastinon (P 2alpha less than 0.05 and 0.01, respectively). The differences demonstrate that tolbutamide Ratiopharm tablets and Rastinon 1,0 Hoechst are not equivalent biologically and therapeutically.

Administration, Oral↗
PubMed1988

Plasma glucose response after intravenous injection of tolbutamide in insulin-treated type I and type II diabetic patients.

To estimate the residual beta-cell function, plasma glucose and C-peptide response to an intravenous injection of tolbutamide were observed in seven Type I (insulin dependent) and nine Type II (non-insulin dependent) diabetic patients on insulin therapy. Fasting plasma glucose in the patient was controlled below 11 mmol/l by conventional insulin therapy, and 1 g of tolbutamide was intravenously injected. In the serum C-peptide response following tolbutamide injection, seven of nine Type II diabetics showed the peak values of serum C-peptide more than 0.3 nmol/l from 20 min to 60 min after the load, and Type I diabetics gained the peak values less than 0.3 nmol/l except one patient. The decrease of plasma glucose within 60 min after tolbutamide injection was more than 20% of the basal level in eight of nine Type II diabetics, and in all of seven Type I diabetics the decrease did not exceed 15%. Both serum C-peptide and plasma glucose after tolbutamide load responded differently between Type I and Type II diabetics on insulin therapy, and it was thought that tolbutamide load-glucose response test may be a useful method to estimate the residual beta-cell function in the diabetics.

Adult↗
PubMed1980

Effects of acute and chronic ingestion of tolbutamide in the chicken.

The effects of acute and chronic ingestion of tolbutamide were studied in the growing chicken. After an oral load of 100 or 25 mg tolbutamide/kg b.w., plasma insulin levels increased in a dose-dependent manner but to relatively low levels for about 10 min, while 10-20 min following tolbutamide, plasma glucose levels were markedly decreased and remained so for 2--5 hr. After 100 mg tolbutamide/kg, the profound hypoglycaemia which developed, was generally accompanied by symptoms resembling an hypoglycaemic coma: panting, muscular flacidity and convulsion. Body temperature and plasma calcium levels were not changed during and after tolbutamide-induced insulin release. In the chicken, tolbutamide response is therefore characterized by a fugitive insulin release and a profound and prolonged hypoglycaemia which suggest that the action of insulin is potentiated by other factors. Chronic ingestion of tolbutamide in the diet transiently (for one week) increased the live body weight of a dose of 400 mg tolbutamide/kg of diet. Long term (5 weeks) fasting plasma glucose levels were unchanged and fasting plasma insulin levels were decreased in the chronic tolbutamide treated chickens.

Animals↗
PubMed1999

Quantitative determination of tolbutamide and its metabolites in human plasma and urine by high-performance liquid chromatography and UV detection.

An isocratic, high-performance liquid chromatography method has been developed for simultaneous determination of the oral antidiabetic tolbutamide and two of its metabolites, 4-hydroxytolbutamide and carboxytolbutamide, in human plasma and urine. The method was based on simple one-step liquid-liquid extraction with tertiary-butyl methyl ether as extraction solvent. The chromatographic eluent was 23:77 (v/v) methanol: 0.01 M aqueous sodium acetate buffer pH 3.0, and the UV detection was performed at a wavelength of 230 nm. The limit of detection was 0.1 microM for tolbutamide in plasma and 1.5 microM, 0.5 microM, and 0.75 microM for carboxytolbutamide, 4-hydroxytolbutamide, and tolbutamide, respectively, in urine. The limit of quantitation was 0.5 micro for tolbutamide in plasma and 2 microM, 0.75 microM, and 1.25 microM for carboxytolbutamide, 4-hydroxytolbutamide, and tolbutamide, respectively, in urine. The overall mean recoveries ranged from 91% to 109% for tolbutamide in plasma and from 80% to 98% in urine for all three compounds.

Chromatography, High Pressure Liquid↗
PubMed1996

Relationship between mephenytoin, phenytoin and tolbutamide hydroxylations in healthy African subjects.

Mephenytoin, phenytoin and tolbutamide are metabolised by the cytochrome P-450 (CYP) 2C family. Recently, it has been shown that phenytoin and tolbutamide are metabolised by CYP2C9/10 whereas mephenytoin is metabolised by CYP2C19. Until now, in vivo studies were only undertaken in Caucasian subjects and showed a strong relationship between phenytoin and tolbutamide metabolism but no significant relationship between the two drug metabolisms and that of mephenytoin. The metabolism of the three drugs was investigated in eight black Africans by urinary analysis. In this ethnic group, a strong relationship was found between phenytoin and tolbutamide oxidations (rs = -0.83, P = 0.01). On the other hand, no significant relationship was found between mephentoin oxidation and phenytoin or tolbutamide oxidations (rs = 0.31 and rs = -0.33, respectively). This study suggests that, in black Africans, phenytoin and tolbutamide but not mephenytoin are also hydroxylated by similar CYP enzyme(s).

Adult↗
PubMed1997

Effects of tolbutamide on ATP-sensitive K+ channels from human right atrial cardiac myocytes.

In order to gain further insight into possible deleterious effects on ischaemia-induced myocardial damage induced by sulfonylureas when administered to humans, the effects of tolbutamide on ATP-sensitive K+ (KATP) channels from human right atrial myocytes were studied. Single myocytes were enzymatically isolated from human right atrium. The cell-attached and inside-out configuration of the patch-clamp technique were employed at room temperature (both the pipette and the bath solution contained high [K+]). KATP channels in inside-out patches showed slight inward rectification, had a slope conductance of 75.1 +/- 2.4 pS (mean +/- S.E.M.; n = 5) at negative membrane potentials and these channels were blocked by ATP (half-maximal block (EC50) at 39 microM; Hill coefficient = 1.65). In cell-attached recordings, cromakalim (300 microM) opened KATP channels (with a slope conductance of 73.3 +/- 1.8 pS (n = 16) at negative membrane potentials) in previously silent patches. Cromakalim-induced openings of KATP channels were not markedly affected by 100 or 300 microM tolbutamide but were blocked by tolbutamide at millimolar concentrations (1-3 mM). The concentration-response relationship for tolbutamide-induced block of KATP channels in the presence of 300 microM cromakalim in cell-attached patches was calculated to values for the EC50 of 1.325 mM and for the Hill coefficient of 1.0, respectively. 1 mM tolbutamide-induced block of cromakalim-induced KATP channel openings was not different at room temperature when compared to 37 degrees. It is concluded that KATP channels from human right atrial myocytes have a low sensitivity towards tolbutamide-induced block.

Adenosine Triphosphate↗
PubMed1978

Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus.

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 mumol/l (100 mug/ml)), yet the variation in dosage was only sixfold (0.5-3.9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 mumol/l (244 mug/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5.4%) of the tolbutamide-treated patients and 10 (16.7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5.5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8.0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.

Adult↗
PubMed1979

Effect of tolbutamide on plasma renin activity.

The effect of tolbutamide on renin secretion in rats was studied in vivo, and in vitro. Administration of tolbutamide in doses of 12.5 and 25 mg/kg body wt ip to two groups of rats produced no significant change in plasma renin activity compared to the control group. In the in vitro experiments renal cortical slices were incubated with increasing concentrations of tolbutamide (0--4 mg/ml). No significant increase in the net renin production was observed, whereas the concentration of cyclic AMP increased significantly in the incubation medium. These findings suggest that in the intact rats tolbutamide does not increase plasma renin activity. In the renal cortical experiments although tolbutamide increased cyclic AMP production, the increase may not have been sufficient to stimulate the net renin production. These results are of biological significance because of the possible effects of tolbutamide and increased plasma renin activity on the cardiovascular system.

Animals↗
PubMed2004

Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is related to two main histological pancreas anomalies: focal adenomatous hyperplasia and diffuse beta-cell hypersecretion. Pharmacological tests to measure acute insulin responses (AIR) to peripheral i.v. injections of glucose, calcium, and tolbutamide have been reported as potential means to distinguish between these histological forms. In patients with defects in ATP-sensitive potassium channels, tolbutamide will fail to induce insulin release in affected portions of the pancreas, whereas calcium gluconate will enhance insulin release through spontaneously active voltage-gated Ca(2+) channels. Consequently, in focal CHI patients, calcium should promote AIRs from the lesion, whereas tolbutamide should act to promote insulin secretion from the healthy region of the pancreas (outside the focal hyperplasia). We therefore studied AIRs to calcium and tolbutamide stimulation tests in 16 children with focal (n = 9) or diffuse (n = 7) CHI before pancreatic surgery. We found hypervariable AIRs to glucose and calcium stimulation in both focal and diffuse CHI patients. AIRs to tolbutamide stimulation were found modest in focal CHI patients, which might account for beta-cell quiescence in the healthy portion of the pancreas of these patients. We conclude that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate the focal from the diffuse CHI patients.

Calcium Gluconate↗
PubMed1981

Differential effects of tolbutamide on first and second phase insulin secretion in noninsulin-dependent diabetes mellitus.

Immunoreactive insulin responses to a 20-g iv glucose challenge during a 7.5 mg/m2/min tolbutamide infusion were studied in 21 untreated noninsulin-dependent male diabetics. All data were analyzed by paired t tests. During the tolbutamide infusion, compared to the saline control period in the same subjects, glucose levels were lowered [217 +/- 17 vs. 196 +/- 16 mg/dl (mean +/- SEM); P less than 0.005], and there was an increase in both first phase (2 +/- 1 vs. 16 +/- 4 micro U/ml; P less than 0.005) and second phase insulin responses (296 +/- 71 vs. 499 +/- 101 micro U. min/ml; P less than 0.05; n = 21). However, when the prestimulus glucose level was lowered by an insulin infusion (214 +/- 20 vs. 145 +/- 17 mg/dl; P less than 0.001), no effect on first phase insulin secretion was observed, and the second phase response decreased (290 +/- 78 vs. 124 +/ 55 micro U. min/ml; P less than 0.005; n = 11; saline control vs. insulin infusion). In 8 subjects, the plasma glucose level during the tolbutamide infusion was kept constant by a concurrent variable glucose infusion. First phase insulin secretion was still increased, though no more than in studies were plasma glucose was not kept constant. However, there was further augmentation of the second phase response (tolbutamide alone, 443 +/- 142 micro U. min/ml; tolbutamide plus glucose, 802 +/- 232 micro U. min/ml; P less than 0.05). These findings indicate that tolbutamide augments first phase insulin secretion in untreated diabetics independently of the prestimulus glucose level. However, changes in the glucose level significantly modulate the sulfonylurea influence on the second phase insulin response to glucose. This effect of glucose level is an important consideration when evaluating the insulinotropic effects of a sulfonylurea.

Adult↗
PubMed1998

Prolonged elimination of tolbutamide in a premature newborn with hyperinsulinaemic hypoglycaemia.

So far, gestational diabetes treated with tolbutamide has never been associated with severe hypoglycaemia in the newborn when the mother's diabetes was well controlled. We report a case of a premature neonate, gestational age 34 weeks, with severe and long-standing hypoglycaemia from birth. The mother had well-controlled gestational diabetes, treated with tolbutamide from the 24th week of gestation until delivery. The neonate had inappropriately high levels of serum proinsulin, insulin and C-peptide relative to blood glucose concentrations. From day 19 after birth, the levels were normalized. Serum tolbutamide was 140.6 micromol/l (38 microg/ml) at 3 h after birth. Zero-order kinetics were seen during the first 90 postnatal hours. The half-life of serum tolbutamide decreased from 46 to 6 h. It is suggested that tolbutamide, when given to the mother until delivery, may cause severe and prolonged hyperinsulinaemic hypoglycaemia in premature neonates. The initially prolonged tolbutamide half-lives and zero-order kinetics suggest immaturity of hepatic elimination during the first 2 days of postnatal life.

Adult↗
PubMed1983

Tolbutamide effect on cultured human endothelial cells with special reference to platelet aggregation.

Since the UGDP report, there have been many discussions on tolbutamide in relation to arterial metabolism. In view of this, we investigated the effect of tolbutamide on endothelial cells using ADP-induced platelet aggregation. We followed Gimbrone's method of cell culture and after the addition of tolbutamide, a platelet aggregation test was performed. 100 microM tolbutamide showed no inhibitory effect on platelet aggregation, but 1 mM tolbutamide effected a 25% decrease in aggregation. These results suggest that tolbutamide does not inhibit prostacyclin synthesis of endothelial cells at conventional dosages.

Adenosine Diphosphate↗
PubMed2006

Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in beta-cells from hyperglycemic mice.

We recently reported that the timing and magnitude of the nutrient-induced Ca(2+) response are specific and reproducible for each isolated beta-cell. We have now used tolbutamide and arginine to test if the cell specificity exists also for the response to non-nutrient stimulation of beta-cells and if so, whether it is disturbed in beta-cells from hyperglycemic ob/ob and db/db mice. Zn(2+) outflow measurements were used to study the correlation between Ca(2+) response and insulin secretion in individual beta-cells. Tolbutamide and arginine induced cell-specific Ca(2+) responses in lean mouse beta-cells both with regard to lag times for [Ca(2+)](i) rise and peak [Ca(2+)](i) heights. beta-Cells within intact islets also showed cell-specific timing of their Ca(2+) responses to tolbutamide. However, in tolbutamide- and arginine-stimulated single beta-cells from ob/ob and db/db mice only the magnitude of Ca(2+) response was cell-specific, not the timing. The lag time of tolbutamide-induced insulin secretion was cell-specific in lean mouse beta-cells but not in ob/ob mouse cells. Therefore, cell specificity seems to be a robust mechanism, and probably important for an adequate beta-cell function. The loss of temporal cell specificity for the response to tolbutamide in single beta-cells from hyperglycemic mice may be a sign of K(ATP)- or voltage-dependent calcium channel dysfunction.

Animals↗
PubMed1997

A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide.

The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide.

1-Naphthylamine↗
PubMed1988

Effect of tolbutamide and glyburide on cAMP-dependent protein kinase activity in rat liver cytosol.

The effect of sulfonylureas tolbutamide and glyburide on adenylate cyclase- and cAMP-dependent protein kinase (A-kinase) was examined in rat liver cytosol. Both tolbutamide and glyburide inhibited the A-kinase activity in a dose-dependent manner. Half-maximal inhibition was obtained at 10 mM with tolbutamide and at 0.2 mM with glyburide, indicating that glyburide was 50-fold as potent as tolbutamide. Neither tolbutamide nor glyburide affected [3H]cAMP binding to the protein kinase, but both inhibited the activity of catalytic units of the A-kinase. Lineweaver-Burk double-reciprocal plots revealed that the inhibitory effects of these drugs were noncompetitive with respect to the protein substrate histone, as well as to the phosphate-donor substrate ATP. Thus, tolbutamide and glyburide inhibited the A-kinase activity in rat liver cytosol, and it was suggested that, through the inhibition of A-kinase, the sulfonylureas would affect the carbohydrate metabolism in the liver. In fact, the relative potencies of these two drugs on A-kinase activity corresponded well with those of their reported antidiabetic effects.

Adenosine Triphosphate↗
PubMed1999

Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel.

ATP-sensitive potassium channels (K(ATP)) are formed from four pore-forming Kir6.2 subunits complexed with four regulatory sulfonylurea receptor subunits (SUR1 in pancreatic beta-cells, SUR2A in heart). The sensitivity of the channel to different sulfonylureas depends on the SUR isoform. In particular, Kir6.2-SUR1 but not Kir6.2-SUR2A channels are blocked by tolbutamide with high affinity. We made chimeras between SUR1 and SUR2A to identify the region of the protein involved in high-affinity tolbutamide block. Chimeric SURs were coexpressed with Kir6.2 in Xenopus oocytes, and macroscopic currents were measured in inside-out membrane patches. High-affinity tolbutamide inhibition could be conferred on SUR2A by replacing transmembrane domains (TMs) 14-16 with the corresponding region of SUR1. Conversely, high-affinity tolbutamide inhibition of SUR1 was abolished by replacing TMs 13-16 with the corresponding SUR2A sequence, or by mutating a single serine residue within this region to tyrosine (S1237Y). Binding of [3H]glibenclamide to membranes expressing SUR1 was abolished concomitantly with the loss of high-affinity tolbutamide block. These results suggest that a site in the COOH-terminal set of TMs of the SUR1 subunit of the K(ATP) channel is involved in the binding of tolbutamide and glibenclamide.

ATP-Binding Cassette Transporters↗
PubMed1992

Cytosolic nucleotides enhance the tolbutamide sensitivity of the ATP-dependent K+ channel in mouse pancreatic B cells by their combined actions at inhibitory and stimulatory receptors.

In the plasma membrane of pancreatic B cells, a K+ channel (K-ATP channel) has been identified that is regulated by cytoplasmic nucleotides. This channel is inhibited by sulfonylureas. We have previously shown that the potency of tolbutamide is much lower in excised membrane patches than in intact cells, unless the internal side of the membrane is exposed to the Mg2+ complex of ADP (MgADP). In the present study, the mechanism of this interactive control by sulfonylureas and nucleotides was examined using the inside-out configuration of the patch-clamp technique. When test solutions containing Mg2+ ions were applied, the opening activity of the K-ATP-channels was strongly stimulated by 2'-deoxyadenosine-5'-diphosphate (dADP) or GDP, slightly stimulated by ADP, and inhibited by adenosine-5'-O-(2-thiodiphosphate) (ADP beta S) or adenylyl-imidodiphosphate (AMP-PNP). In the presence of Mg2+, not only ADP but also its analogues dADP (1 mM) and ADP beta S (0.1 mM) enhanced the potency of tolbutamide for channel inhibition; dADP at a low concentration (0.2 mM), GDP (0.2-1 mM), and AMP-PNP (0.2 mM) did not alter the potency of tolbutamide. The particular feature of the test solutions that enhanced the potency of tolbutamide was the presence of Mg(2+)-bound and free nucleotides at channel-stimulating and channel-inhibiting concentrations, respectively. In the presence of Mg2+ and 0.2 mM dADP or 0.2-1 mM GDP, 0.2 mM AMP-PNP intensified the response to tolbutamide by serving as channel-inhibiting component. MgAMP-PNP did not stimulate the opening activity of the K-ATP channel. The sensitivity to tolbutamide that was enhanced by a submaximally effective ADP concentration was further increased by AMP-PNP or ATP but not by GDP. The sensitivity to the sulfonylurea analogue meglitinide was also enhanced by ADP. It is concluded that nucleotides inhibit and activate the K-ATP channel by interaction with two separate receptor sites at the cytoplasmic face of the B cell membrane. Effective inhibition of the channel openings by sulfonylureas results from the simultaneous occupation of both sites by appropriate nucleotides.

Adenine Nucleotides↗
PubMed1977

The effect of tolbutamide on contractility and cyclic adenosine 3':5'-monophosphate concentration in the intact beating rat heart.

The effect of tolbutamide on contractility and the concentration of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in ventricular muscle was examined in the intact beating rat heart. The hearts were perfused in a nonrecirculated (Langendorff) fashion. Bolus injections of tolbutamide caused an increase in cardiac contractility. This increase in contractility was markedly inhibited when bovine albumin (3 g/100 ml) was present in the perfusing fluid. The increase in contractility caused by tolbutamide was not preceded by or associated with any change in the concentration of cyclic AMP in the ventricular muscle. Further studies utilizing a simultaneous injection of norepinephrine and tolbutamide demonstrated no significant effect of this combination on the concentration of cardiac cylcic AMP produced by an injection of norepinephrine alone. Our findings suggest that in the intact beating rat heart the positive inotropic effect of tolbutamide is not mediated via an increase in the concentration of cardiac cyclic AMP and that tolbutamide does not significantly potentiate the effect of catecholamines on cardiac cyclic AMP concentration.

Albumins↗