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PubMed1979

Tolbutamide pharmacogenetics and the UGDP controversy.

We analyzed the relationship between the pharmacogenetics of tolbutamide metabolism and the controversial University Group Diabetes Program (UGDP) study. Before the institution of that study, the extent of genetic control over the variation in the rate of tolbutamide metabolism was unknown, and all subjects included in the tolbutamide treatment group were given 1,500 mg/day of tolbutamide in a fixed dosage. We addressed the hypothesis that high accrued blood levels of tolbutamide in genetically predisposed slow inactivators might have contributed to the toxic effects reported by the UGDP study. This proposal is based on recent findings from population, twin, and family studies that tolbutamide metabolism is under monogenic control, with nearly one fourth of the population classified as slow inactivators.

Alleles↗
PubMed1979

Spectrophotometric determination of tolbutamide in tablets.

Two spectrophotometric methods, Glenn's method of orthogonal function and the basic dye method, are described for determing tolbutamide in tablets without interference from the tablet excipients. In Glenn's method, the absorbance of tolbutamide in 95% ethanol is measured in the vicinity of 250--270 nm at 4 nm intervals and the p2 coefficient is calculated. The coefficient is linearly related to concentration within a range of 0.1--0.4 mg/mL. Tolbutamide gives a complex of a ratio 1:1 with basic dye Brilliant Cresyl Blue (BCB) or Safranin T (ST). The complex is easily extracted with chloroform. The absorbance of the chloroform extract is measured against either a blank or reference experiment. The latter is obtained by using a specific concentration of tolbutamide: 0.4 mg/mL in tolbutamide-BCB or 0.024 mg/mL in tolbutamide-ST. The ST complex method is more sensitive compared with the other methods. When the t-test is applied, the results of the proposed methods are more accurate than those of the traditional ultraviolet spectrophotometric method.

Coloring Agents↗
PubMed1979

[Drug interaction during therapy with tolbutamide. The influence of some commonly used drugs on plasma level and half life in diabetic out-patients (author's transl)].

Tolbutamide belongs to those drugs responsible for the majority of drug interactions. E.g. Tolbutamide metabolism has been shown to be inhibited by coumarole derivatives. We determined plasma-tolbutamide levels in diabetic out-patients for one year. The results obtained indicate no difference in patients additionally treated with either digoxin or digoxin and alpha-methyldopa, or buformin and phenprocumone as compared with control groups. Interactions with respect to biotransformation should not be expected as far as digoxin, alpha-Methyldopa, or buformine were concerned, since these compounds do not share a common metabolic pathway with tolbutamide. In a different group of patients the elimination half life of tolbutamide under the influence of phenprocoumone was additonally determined. Differences could not be detected. This finding can be explained by means of enzyme-kinetic considerations, since phenprocumone, in contrast to dicoumarole, becomes metabolized according to a first order reaction. Competitive enzyme inhibition with tolbutamide which is metabolized similarly to phenprocoumone, therefore appears improbable.

Buformin↗
PubMed1995

Effect of tolbutamide on the rate of fatigue and recovery in frog sartorius muscle.

The goal of this study was to determine how blocking ATP-sensitive K+ channels with tolbutamide affects the excitability and contractility of intact frog sartorius muscle during fatigue development. Fatigue was elicited with one tetanic contraction every sec for 3 min. During fatigue the resting potential decreased by 10 mV although the action potential overshoot remained constant. The addition of 2 mmol.liter-1 tolbutamide 60 min before fatigue did not modify the effect of fatigue on the resting potential and action potential overshoot. During fatigue development the half-repolarization time of control muscles increased by 0.26 msec in control muscles, although it increased by 0.77 msec in the presence of 2 mmol.liter-1 tolbutamide; the difference was significant. The decrease in force during fatigue development was not affected by 2 mmol.liter-1 tolbutamide (added 60 min before fatigue), whereas the recovery of force after fatigue was slower in tolbutamide- exposed muscles than in control muscles. Addition of 2 mmol.liter-1 tolbutamide after 5 min of recovery reduced the recovery rate of the resting potential and half-repolarization time, but did not affect the recovery of tetanic force during the first 40 min. Our results are consistent with the hypothesis that ATP-sensitive K+ channels are activated during fatigue development and that they contribute to the repolarization phase of action potentials, but they do not support the hypothesis that ATP-sensitive K+ channels contribute to the decrease in force.

Action Potentials↗
PubMedDate not supplied

A species comparison of tolbutamide metabolism in precision-cut liver slices from rats and dogs. Qualitative and quantitative sex differences.

Precision-cut liver slices from rats and dogs were used to investigate in vitro the metabolism of tolbutamide. Tolbutamide (100 microM) was incubated with liver slices in 12-well plates (rat: 1 slice/well; dog: 4 slices/well) for up to 9 hr. In rats, qualitative sex differences were found in tolbutamide metabolism, whereas in dogs quantitative sex differences were found. In male and female rats, the major metabolite was hydroxytolbutamide, with minor amounts of carboxytolbutamide. In both sexes, the formation rates of these metabolites were the same. In male rats, also the "dog-specific" metabolites, p-tolylsulfonylurea and p-tolylsulfonamide, were found. No direct toxicity of tolbutamide and its metabolites was observed. In male and female dogs, the major metabolite was p-tolylsulfonylurea, with smaller amounts of hydroxy- and carboxytolbutamide. Formation rates of the various tolbutamide metabolites in male dogs were approximately 3 times higher than in female dogs. The "dog-specific" metabolite p-tolylsulfonamide could not be detected. These results show that precision-cut liver slices are capable of detecting hitherto unknown species and sex differences in the metabolism of tolbutamide. Liver slices are a promising in vitro method for the study of comparative drug metabolism.

Animals↗
PubMed1993

The influence of tolbutamide on fatty acid metabolism in the liver and muscle.

Metabolism of palmitate-14C was studied in the rat liver and muscle incubated with 1 mmol.l-1 tolbutamide in vitro experiments: Tolbutamide reduces the utilization of free fatty acids in the liver by inhibiting their uptake, incorporation into total lipids, and oxidation to 14CO2. Tolbutamide stimulates the incorporation into the triacylglycerol fraction in individual liver lipid fractions and inhibits the incorporation into the free fatty acid fraction. As in the liver, tolbutamide inhibits the uptake, incorporation into total lipids, and oxidation to 14CO2 in the muscle. In individual lipid fractions, tolbutamide only inhibits the incorporation of palmitate into cholesterol esters. It can be concluded that tolbutamide directly interferes with fatty acid metabolism and thus improves glucose utilization and insulin resistance.

Animals↗
PubMed1977

Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide.

To study the influence of acute hepatic disease on the disposition of tolbutamide, we measured tolbutamide plasma protein binding and pharmacokinetic parameters after intravenous administration of the drug to 5 subjects during and after apparent recovery from acute viral hepatitis. Although during the acute phase of illness protein binding of the drug decreased in all, volume of distribution of tolbutamide (0.15 +/- 0.03 L/kg) did not change. Clearance based on total concentration of tolbutamide in plasma increased in all subjects during the acute phase of study (26 +/- 5.4 ml/hr/kg) in comparison to the recovery phase (18 +/- 2.8 ml/hr/kg, p less than 0.02). Protein binding decreased after unconjugated bilirubin was added to plasma from the recovery phase, but not to the extent observed during the acute phase of illness at comparable levels of bilirubin. Clearance based on unbound drug concentration, calculated by dividing the observed plasma clearance by the fraction of unbound drug in plasma, did not differ significantly between the 2 study phases (300 +/- 47 and 260 +/- 39 ml/hr/kg). These observations suggest that the increase in clearance based on total drug concentration in plasma during hepatitis can be attributed solely to decreased plasma binding. This decrease in binding may be attributed in part, but not entirely, to increased combination of bilirubin during illness. The concentration of unbound drug in plasma at steady-state is determined by the rate of drug administration and the clearance based on unbound drug. If this clearance does not change during hepatic disease, no dosage alterations for tolbutamide and other comparable drugs are necessary to maintain a constant concentration of unbound drug.

Acute Disease↗
PubMedDate not supplied

Inhibition of tolbutamide elimination by cimetidine but not ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on tolbutamide pharmacokinetics. Twelve healthy men were given a 1-g oral dose of tolbutamide on three occasions. Subjects were randomly assigned to three treatments in a crossover fashion: cimetidine 1,200 mg/d, ranitidine 300 mg/d, and placebo. Cimetidine significantly increased the tolbutamide area under the plasma concentration-time curve by 20% (range, -5% to 42%), increased the elimination half-life by 17%, and decreased the carboxytolbutamide:tolbutamide plasma ratio from 0.042 to 0.036. Ranitidine did not significantly alter tolbutamide pharmacokinetics.

Adult↗
PubMed1993

The inhibitory effect of tolbutamide on phosphoenolpyruvate carboxykinase activity in rat hepatoma H4IIE cells.

Effects of tolbutamide on the activity of hepatic phosphoenolpyruvate carboxykinase (PEPCK), a rate limiting enzyme in gluconeogenesis, was examined using rat hepatoma (H4IIE) cells. Tolbutamide inhibited PEPCK activity induced by cAMP in a time- and dose-dependent manner. Tolbutamide effect was rapidly exerted and insulin-independent. The inhibitory effect of 5 mM tolbutamide corresponded with that of 10(-7) M insulin. These results suggest the possibility that tolbutamide plays a significant role on amelioration of the deranged glucose metabolism in the liver through repression of gluconeogenesis, primarily due to the inhibition of PEPCK activity.

Animals↗
PubMed1992

Effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide.

The effect of magnesium hydroxide on the absorption and efficacy of tolbutamide and chlorpropamide was examined in a total of 32 healthy volunteers in two separate, randomized parallel-group studies, with 16 subjects in each study. After an overnight fast, the first group of 8 volunteers ingested 500 mg tolbutamide or 250 mg chlorpropamide with 150 ml water, and the second group the same doses of the active drugs with 150 ml water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the area under the plasma tolbutamide concentration-time curve (AUC) from 0 to 1 h and from 0 to 2 h by 5-fold and 2.5-fold, respectively. The peak plasma concentration, peak time and total AUC were not significantly altered. The incremental insulin area and the decremental glucose area from 0 to 1.5 h were significantly larger in the magnesium hydroxide group than in the controls. The maximum insulin response to tolbutamide was increased fourfold by coadministration of magnesium hydroxide, and it occurred about 1 h earlier than in the control group. In addition, the maximum fall in plasma glucose concentration was attained about 1 h earlier in the antacid group. A tendency to an increased rate of chlorpropamide absorption was observed after magnesium hydroxide, but it did not appear to affect the insulin and glucose responses to chlorpropamide. It is concluded that magnesium hydroxide increased the early bioavailability of tolbutamide, resulting in enhanced insulin and glucose responses. A tendency toward accelerated chlorpropamide absorption by magnesium hydroxide was also observed, but the efficacy of chlorpropamide was unaffected.

Adult↗
PubMed1981

Potentiation of the insulin-releasing capacity of tolbutamide by thiols: studies on the isolated perfused pancreas.

It has been suggested that the islet thiol redox status plays a role in the regulation of beta-cell sensitivity in response to insulin secretagogues. Employing the isolated perfused rat pancreas, the effect of reduced glutathione (1 mM) and L-cysteine (5 mM) on insulin release induced by tolbutamide (0.2 mg/ml), glucose (5.6 and 11.1 mM) and tolbutamide (0.1 mg/ml) in the presence of 5.6 mM glucose was studied. In the absence of glucose or in the presence of 5.6 mM of glucose neither glutathione nor L-cysteine stimulated the release of insulin. Reduced glutathione potentiated the secretion induced by glucose (11.1 mM) during the first and the second phase. L-Cysteine potentiated only the first phase of glucose-induced insulin release, whereas the second phase was depressed. Both of the tested thiols potentiated the insulin secretory action of either tolbutamide (0.2 mg/ml) alone or tolbutamide (01. mg/ml) in the presence of glucose (5.6 mM). The data suggest that supplementation of thiols to the pancreatic beta-cells perse cannot initiate the insulin secretory process. It is also suggested that GSH and L-cysteine increase the sensitivity of beta-cells to the stimulatory action of tolbutamide and/or glucose.

Animals↗
PubMed1983

Effect of activated charcoal on absorption of tolbutamide and valproate in man.

The claim that activated charcoal should be ineffective or even contraindicated in intoxication due to tolbutamide is based only on limited in vitro studies. To test the claim, the effect of activated charcoal 50 g on the absorption of tolbutamide and, as a reference, of sodium valproate, was studied in 6 healthy volunteers. Each volunteer swallowed tolbutamide 500 mg and sodium valproate 300 mg with 50 ml water 1 h after a light breakfast, and within 5 min they took in randomized order either a suspension of activated charcoal or water. The absorption of tolbutamide, calculated as the peak concentration and the area under the serum drug concentration-time curve during 0-48 h, was reduced by 90% by charcoal (p less than 0.001). The absorption of valproate in these conditions was reduced on average by 65% (p less than 0.01). In each subject charcoal had a greater effect on the absorption of tolbutamide than of valproate. According to these findings and preliminary in vitro studies on other sulphonylureas high doses of activated charcoal can be recommended for the preventing the absorption of sulphonylureas in acute intoxications. The poor aqueous solubility of these substances at the gastric pH probably delays their gastrointestinal absorption, so that they may be adsorbed on to charcoal even given several hours later.

Adult↗
PubMed1988

Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide.

The effects of sulphaphenazole, cimetidine and primaquine on the disposition of antipyrine and tolbutamide in healthy volunteers have been investigated. The model substrates were administered simultaneously in order more clearly to define any selective effects of the potential inhibitors. Sulphaphenazole produced a significant increase in the half-life of tolbutamide (7.10 to 21.50 h) and a corresponding decrease in its clearance (0.260 to 0.084 ml.min-1.kg-1). Clearance to hydroxytolbutamide (OHTOL) and carboxytolbutamide (COOHTOL) was also significantly decreased. In contrast, sulphaphenazole had no effect on the disposition of antipyrine. Administration of cimetidine did not significantly alter the disposition of either model drug. However, a 1.6-times higher dose of cimetidine did increase the half lives both of tolbutamide and antipyrine (6.21 to 9.04 h and 14.2 to 19.2 h, respectively) and decrease their clearance (0.226 to 0.148 and 0.50 to 0.31 ml.min-1 kg-1, respectively). Clearance to OHTOL and hydroxymethylantipyrine (HMA) was reduced. A single dose of primaquine had no demonstrable effect on tolbutamide disposition whereas the half-life of antipyrine was increased (12.1 to 15.0 h) and its clearance decreased (0.63 to 0.38 ml.min-1.kg-1). The partial clearance to HMA, 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was also significantly reduced. The two main inferences are first, that tolbutamide and antipyrine are metabolised by different forms of cytochrome P-450, and second that a battery of model substrates is needed to investigate the inhibitory effects of a drug in man.

Adult↗
PubMed1980

Glipizide versus tolbutamide, an open trial. Effects on insulin secretory patterns and glucose concentrations.

An open parallel trial with glipizide or tolbutamide was carried out in a cohort of 29 comparable maturity-onset diabetic patients. Eighteen of these individuals were studied in detail. During six months of active drug therapy the mean decrease in fasting serum glucose levels on glipizide was 25 +/- 2% versus 17 +/- 2% on tolbutamide (p less than 0.025). Decreases in post prandial glucose levels were 12.2 and 10.4%. Glucose disappearance rates (Kg) during the sixth month of treatment with both drugs increased significantly: on glipizide from 0.47 +/- 0.04%/min to 0.85 +/- 0.08%/min(p less than 0.005), and on tolbutamide from 0.47 +/- 0.08%/min to 0.70 +/- 0.11%/min (p less than 0.01). Early and late insulin release (summed increases over basal for 2--10 min and 10--60 min) during intravenous glucose tolerance testing increased during glipizide, but not during tolbutamide therapy. Post prandial insulin increments over basal during an oral glucose tolerance test also increased during glipizide, but not tolbutamide therapy. Both drugs were comparable with regard to efficacy and safety; however, only glipizide had chronic effects upon insulin secretion.

Aged↗
PubMedDate not supplied

Potentiation of the pressor response to stress by tolbutamide in dogs.

Tolbutamide has previously been shown to amplify the pressor effects of "exogenous" catecholamines in conscious dogs, possibly due to sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. The objective of this study was to examine if tolbutamide also amplifies the pressor effects of "endogenous" catecholamines released during psychological stress (classical Pavlovian aversive conditioning). Experiments were conducted in beta-adrenoreceptor-blocked (propranolol, 1 mg/kg, i.v.) conscious dogs (n = 4) trained in classical aversive conditioning. Conditioning was accomplished by following a tone (CS+) with a 1/2 second shock; another tone (CS-) was not followed by any shock and served as control. With saline pretreatment, aversive conditioning (i.e., CS+) increased mean arterial pressure (MAP) only by approximately 4.7% when compared to CS-, whereas with tolbutamide (45 mg/kg, i.v.) pretreatment, the increase in MAP induced by CS+ beyond what was induced by the CS- (approximately 6.2%) was significantly (p < 0.05) larger than that with saline pretreatment. In isolated canine femoral arterial segments (n = 4), the vasoconstrictor effect of phenylephrine (an alpha 1-agonist) at 5 x 10(-6) M (which was the EC50 value) was amplified by 2 x 10(-2) M of tolbutamide from 54.0 +/- 2.0% to 66.9 +/- 2.1%. In conclusion, tolbutamide amplifies the pressor effects of "endogenous" catecholamines in conscious dogs, possibly by sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. This mechanism of action is novel and has not been reported with other agents.

Animals↗
PubMed1996

A drug interaction study between cicletanine and tolbutamide in healthy volunteers.

OBJECTIVE: To determine the possible interaction between the antihypertensive agent cicletanine and the hypoglycaemic drug tolbutamide. METHODS: Time-courses of glycaemia and serum immunoreactive insulin (IRI) were followed in 10 healthy subjects after two tolbutamide infusions in each volunteer; initially alone and 9 days later concomitantly with repeated oral cicletanine. Any drug interaction was quantified on the basis of a decrease or increase in the AUC with time of glycaemia and IRI by subtraction of baseline concentration (AUC0(240)-GLY and AUC0(60)-IRI). Peak glycaemia and peak IRI, and the corresponding time to peaks, were also assessed. RESULTS: Following tolbutamide, mean AUC0(240)-GLY values were 97.7 and 98.8 mmol.l-1.min, without or with cicletanine, respectively; the corresponding AUC0(60)-IRI were 485 and 321 mU.l-1.min. Mean peak glycaemia values were 0.996 and 1.071 mmol.l-1. Regarding the peak IRI, a decrease was observed after tolbutamide and cicletanine: median values were 29.2 and 17.4 mU.l-1. The corresponding median time to peak glycaemia and IRI values were 30 and 30 min and 5 (all subjects) and 5 min. CONCLUSION: No clinically relevant interaction was shown after the concomitant administration of repeated oral doses of cicletanine and acute intravenous tolbutamide to healthy volunteers.

Administration, Oral↗
PubMed1999

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes.

OBJECTIVE: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. METHODS: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. RESULTS: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (Km) of 133 microM and a mean apparent maximal velocity (Vmax) of 248 pmol x min(-1) x mg(-1); formation of 7-hydroxywarfarin yielded a mean Km of 3.7 microM and a mean Vmax of 10.5 pmol x min(-1) x mg(-1). Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (Ki) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4-17.3) microM and 13.0 (8.4-18.7) microM, respectively. The average Ki value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0-125) microM. CONCLUSION: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism.

Adult↗
PubMed1996

Effects of glucose, forskolin and tolbutamide on membrane potential and insulin secretion in the insulin-secreting cell line INS-1.

Membrane voltages (Vm) of INS-1 cells, an insulin-secreting cell line, were measured mostly using the cell-attached mode of the patch-clamp method. The cell-attached configuration allowed the cell to be kept intact. Measurement of Vm was possible because seal resistances were very high and because the membrane obviously had a sufficiently high conductance (probably via K+ channels). Resting Vm was -80 +/- 1 mV (n = 42) and was mainly determined by sulphonylurea-sensitive K+ATP channels since tolbutamide depolarized the plasma membrane in a concentration-dependent manner and generated action potentials at 50 and 100 micromol/l. D-Glucose, tested between 0.5 and 16.7 mmol/l, also depolarized the plasma membrane in a concentration-dependent manner and induced action potentials at concentrations higher than 5.6 mmol/l. Similarly, forskolin (5 micromol/l) depolarized the cells and increased the frequency of Ca2+-mediated action potentials. Insulin secretion was measured from cells growing in culture dishes, by radioimmunoassay. Glucose doubled secretion in INS-1 cells, whereas tolbutamide had no significant effect on secretion in the presence of 0.5 mmol/l and 16. 7 mmol/l glucose. At 3 mmol/l glucose, tolbutamide increased insulin release slightly. Forskolin elevated secretion twofold at a low glucose concentration. In contrast, when glucose or tolbutamide were added together with forskolin secretion was potentiated five- to tenfold. These results show that glucose induces membrane activation in INS-1 cells. Furthermore, the potent effect of tolbutamide, i.e. to depolarize the plasma membrane without inducing insulin release, leads to the conclusion that effects distal to depolarization are pivotal for secretion in INS-1 cells.

Action Potentials↗