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PubMed1964

RATES OF DISSOLUTION OF TOLBUTAMIDE TABLETS.

An investigation was made of the pharmaceutical properties and the in vitro dissolution rates of 18 commercially available brands of tolbutamide tablets, all of which met the limits set by the Food and Drug Regulations for tablets sold in Canada.A marked variation in dissolution rates was found, which bore no relation to the official disintegration time. These wide variations in dissolution rate point to a need for (a) a comprehensive study of the in vivo effects of different tolbutamide tablets, and (b) an official test that sets limits for the rate of dissolution of tolbutamide tablets, in addition to the one that places limits on disintegration time.

Absorption↗
PubMed1965

A COMPARATIVE STUDY OF SOME BRANDS OF TOLBUTAMIDE AVAILABLE IN CANADA. I. CLINICAL ASPECTS.

Two lots of brand-name and three lots of non-proprietary tolbutamide products, the latter having been reported to be clinically ineffective, were compared in a double-blind study in 22 diabetic patients. Every patient took each of the five brands for two weeks. The dose range was 1 to 2 g. per day and the dose was kept constant in each patient throughout the five test periods. Statistical analyses of fasting, mid-morning and mid-afternoon blood sugar levels, mid-morning and mid-afternoon blood tolbutamide levels and levels of tolbutamide and its metabolite in 24-hour urine did not show any significant differences among the five products except for better control of fasting blood-sugar levels by one brand, nor did clinical observations reveal any differences.

Biomedical Research↗
PubMed1975

Inotropic action of tolbutamide on human myocardium.

The inotropic action of tolbutamide previously demonstrated in vitro was evaluated in 15 nondiabetic subjects during diagnostic cardiac catheterization. Following bolus injection of 250 mg of tolbutamide intravenously, a rise of serum insulin and a slight fall of serum potassium were observed. Inotropic response was determined from significant fall in PEP/LVET ratio, significant fall of left ventricular end-diastolic pressure, shift to an augmented function curve in work-pressure relationships, and prominent rise of dP/dt values at comparable heart rates. The inotropic effect was greatest at 5-15 min with return to near control values at 30 min. An unusually marked inotropic response was observed in one subject. While the measurable net hemodynamic effect of tolbutamide in the human heart is small, its effect on ischemic and normal areas within the heart of a diabetic patient with atherosclerosis may be different. Thus, its ultimate effect on the diseased heart may be significant.

Blood Glucose↗
PubMed1975

Unaltered metabolism of antipyrine and tolbutamide in fasting man.

Effects of fasting on the metabolsim and distribution of antipyrine and tolbutamide were studied in 13 obese, but otherwise healthy, volunteers. Only 6 of the 13 subjects decreased their metabolic clearance rate (MCR) during fasting; no significant change occurred during fasting in the mean MCR of either drug. These results are in contrast with reported changed rates of drug metabolism in fasting experimental animals. The apparent volume of distribution (aVd) of antipyrine decreased during fasting in each of 7 subjects receiving oral test doses of antipyrine; the mean control value plus or minus standard deviation was 61 plus or minus 16 1, whereas during fasting the mean became 52 plus or minus 17 1. The aVd plus or minus SD of tolbutamide decreased in 4 of the 6 volunteers receiving intravenous test doses of tolbutamide; the mean control value in these6 volunteers was 8.3 plus or minus 1.7 1; during fasting it was 7.4 plus or minus 1.91.

Administration, Oral↗
PubMed1976

GLC determination of plasma levels of intact chlorpropamide or tolbutamide.

A GLC procedure was developed for the quantitative estimation of intact chlorpropamide and tolbutamide concentrations in plasma; the drugs are used as mutual internal standards. After extraction of plasma containing the drug and internal standard with toluene, the dried residue is treated with ethereal diazomethane to form the methyl derivatives of tolbutamide and chlorpropamide. Aliquots of the ethereal solution are injected into a gas chromatograph equipped with a glass-lined injection port and glass column packed with a phenyl methyl silicone fluid (OV-25) on Chromosorb W, which facilitates the intact determination of the methyl derivatives of the drugs. The response to the flame-ionization detector was linear over a range of 0.20-25 mug/ml, with a 0.05-mug/ml limit of detectability for both drugs. The method compares favorably with a recently developed high-pressure liquid chromatographic procedure and is adequate for following blood level profiles of single doses of chlorpropamide (125 mg) and tolbutamide (250 mg). Mass spectral evidence showing that intact sulfonylureas are measured is presented.

Biological Availability↗
PubMed1979

Stability-indicating high-performance liquid chromatographic determination of chlorpropamide, tolbutamide, and their respective sulfonamide degradates.

A quantitative high-performance liquid chromatographic method for the determination of chlorpropamide, tolbutamide, and their respective hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, in solid dosage forms was developed. The method is stability indicating and can be used to determine the sulfonamide hydrolysis product and the intact drug in the presence of minor degradates. Method reproducibility, demonstrated by repeated injections of a calibration standard, was 1.21%. The lower limit of quantitation of the hydrolysis products, p-chlorobenzenesulfonamide and p-toluenesulfonamide, was 0.2 microgram/5-microliter injection. The accuracy of the method for intact drugs was determined by comparison of the HPLC results to those obtained by the appropriate USP or BP assays. The mean of the results obtained by the two methods differed by 0.7% for chlorpropamide and 0.3% for tolbutamide. Pure drug samples were spiked with amounts of the hydrolysis products ranging from 20 to 120% of the intact content. The mean percent recovery for p-chlorobenzenesulfonamide was 98.6%; for p-toluenesulfonamide, it was 100.6%. A qualitative TLC procedure for the detection of chlorpropamide, p-chlorobenzenesulfonamide, dipropylurea, propylurea, n-propylamine, tolbutamide, p-toluenesulfonamide, dibutylurea, butylurea, and n-butylamine is also described.

Chlorpropamide↗
PubMed1979

Effects of phenylbutazone, tolbutamide, and clofibric acid on binding of racemic warfarin and its enantiomers to human serum albumin.

The effect of phenylbutazone, tolbutamide, and clofibric acid on the binding of racemic warfarin and its enantiomers to human serum albumin was studied by equilibrium dialysis. Warfarin had one primary and two secondary binding sites on the albumin molecule. No difference in binding was detected at the primary binding site; the extent of R(+)-isomer binding at the secondary binding sites was 2.5 times greater than the corresponding S(-)-isomer binding. Phenylbutazone and warfarin appear to compete for the same primary binding site on the albumin molecule. Tolbutamide interferes with the binding of warfarin enantiomers at their secondary sites. Clofibric acid has a less pronounced effect on warfarin binding than does phenylbutazone or tolbutamide.

Binding, Competitive↗
PubMed1982

Combined water-soluble carriers for coprecipitates of tolbutamide.

A study was conducted on the influence of single and combined carriers on the dissolution rate of tolbutamide from its coprecipitates. All of the water-soluble carriers investigated enhanced the dissolution rate of tolbutamide, but the combination of 40% polyethylene glycol 6000--60% dextrose as the carrier for a 1:1 coprecipitate yielded the most rapid dissolution of tolbutamide. Other carriers used were polyethylene glycol 6000, polyethylene glycol 4000, dextrose, and mannitol, alone or combined in various proportions.

Chemical Precipitation↗
PubMed1984

Crystallinity and dissolution rate of tolbutamide solid dispersions prepared by the melt method.

The influence of cooling rate of solid dispersions prepared by the melt method was studied by X-ray diffraction and scanning electron microscopy. Tolbutamide was the model drug investigated, and the carriers included urea and polyethylene glycol 6000. Slow-cooled urea dispersions of tolbutamide demonstrated a complete lack of crystallinity, suggesting the formation of an amorphous material. The rapidly cooled dispersion showed peaks for urea and an absence of drug in the X-ray pattern, suggesting that a true molecular dispersion was formed. The X-ray patterns of rapid- and slow-cooled dispersions of tolbutamide and polyethylene glycol 6000 demonstrated that a physical mixture of drug and carrier resulted from both methods of dispersion preparation.

Chemical Phenomena↗
PubMed1985

Effect of food and tablet age on relative bioavailability and pharmacodynamics of two tolbutamide products.

Relative bioavailability and pharmacodynamics of tolbutamide from two different commercially available tablet products have been evaluated in healthy subjects in a single-dose crossover study. "Fresh" tablets and tablets aged by exposure to 98% relative humidity for 3 d at ambient temperature were studied. Aging was found to differentially affect both the rate and extent of absorption for the two products. Differences were reflected by log AUC (generic product AUC 10% lower than the product of the innovator, p = 0.047), peak concentration (generic product 27% lower than the product of the innovator, p = 0.0001), mean absorption time (generic product 119% longer than the product of the innovator, p = 0.0008), and mean residence time (generic product 17% longer than the product of the innovator, p = 0.011). Aged product from the innovator produced statistically significantly higher serum tolbutamide concentrations for the first 8 h postdose and a greater glucose depression than aged generic product. Administration of unaged tablets with food produced differences in the rate of absorption, manifested in time-to-peak (generic product 69% later than the product of the innovator, p = 0.006), peak concentration (generic product 18% lower than the product of the innovator, p = 0.001), and mean absorption time (generic product 104% greater than the product of the innovator, p = 0.007), which resulted in statistically significantly higher tolbutamide concentrations for the product of the innovator than for the generic product for the first 3 h postdose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

The regulation of glucose-induced insulin secretion by pre-stimulus glucose level and tolbutamide in normal man.

The relationship between the pre-stimulus glucose level and immunoreactive insulin responses to a glucose challenge (20-g IV) was studied in normal subjects. When the steady-state pre-stimulus glucose concentration was lowered by a 0.33 mU.kg-1.min-1 insulin infusion or raised by a 900 mg/min glucose infusion, no effect on first phase insulin secretion (mean delta 3-5 min insulin level) was observed. In contrast, the second phase response (10-60 min insulin area after glucose pulse) to intravenous glucose fell during insulin infusion and increased during the glucose infusion. Overall, a linear relationship was found between the change of pre-stimulus glucose or level from the control to that during the insulin or glucose infusion and the change in second phase response (r = 0.65, n = 14, p less than 0.02). The effect of tolbutamide infusion (7 mg.m-2.min-1) when compared with saline control was to increase both first phase (+54 +/- 13 mU/l, n = 8, p less than 0.001, mean +/- SEM) and second phase (+972 +/- 256 mU. min-1.l-1, p less than 0.01) insulin secretion. It is concluded that the first phase response to a glucose pulse is independent of the steady-state pre-stimulus glucose concentration and is directly enhanced by tolbutamide; in contrast, second phase is related to both the steady-state pre-stimulus glucose level and tolbutamide. These findings suggest that changes in basal or pre-stimulus plasma glucose during therapy with sulphonylurea drugs may be expected to influence the second phase insulin responses to glucose challenge.

Adult↗
PubMed1984

Tolbutamide does not alter insulin requirement in Type 1 (insulin-dependent) diabetes.

We examined whether tolbutamide has any acute or short-term effects on insulin action in Type 1 (insulin-dependent) diabetes. A euglycaemic glucose clamp was performed in seven Type 1 diabetic patients without clinical insulin resistance by infusing glucose at a constant rate of 0.01 mmol X kg-1 X min-1 for 3h together with a simultaneous insulin infusion using an 'artificial pancreas'. The insulin infusion rate required to maintain blood glucose at 6.7 mmol/l at a set low glucose infusion rate provides an index of insulin action in vivo. The euglycaemic clamp was performed on 3 separate days in the same patient: (1) in the basal state; (2) during simultaneous intravenous tolbutamide infusion of 0.5 g/h, and (3) after treatment with 2.5 g tolbutamide/day for 6 days in addition to insulin. The insulin infusion rate needed to maintain the set blood glucose level did not differ significantly between the three experimental conditions (1.2 +/- 0.2 versus 1.3 +/- 0.3 versus 1.2 +/- 0.3 U/h). Plasma glucagon, growth hormone, non-esterified fatty acid and glycerol levels did not differ between control or sulphonylurea treatment studies. The results suggest that tolbutamide does not exert any acute or short-term effects on insulin action in vivo in Type 1 diabetes. Our results do not provide support for the idea that this agent is a clinically useful adjunct to insulin in such patients.

Adult↗
PubMed1989

The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells.

The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 mumol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 mumol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.

Adenosine Triphosphate↗
PubMed1990

Tolbutamide reverses membrane hyperpolarisation induced by activation of D2 receptors and GABAB receptors in isolated substantia nigra neurones.

A high density of binding sites for sulphonylureas is found in the substantia nigra. These binding sites may be linked to ATP-regulated K-channels (K-ATP channels) as sulphonylureas selectively inhibit these channels in pancreatic beta-cells. We have studied the effect of the sulphonylurea tolbutamide on the electrical properties of freshly isolated neurones from guinea-pig substantia nigra, using the perforated patch technique. In spontaneously firing cells, both the D2 agonist quinpirole and the GABAB agonist baclofen abolished firing, hyperpolarised the cell and increased the whole-cell conductance. Tolbutamide reversed all three effects, but was without effect in the absence of quinpirole or baclofen. We suggest that D2 and GABAB receptors activate a K-channel that is blocked by tolbutamide.

Animals↗
PubMed1975

Tolbutamide-induced changes of the DNA, protein and insulin content and the secretory activity of isolated rat pancreatic islets.

Following prolonged administration of tolbutamide the DNA- and protein content per islet was enhanced but the IRI content per islet was diminished. Glucose-induced (2.0, 8.0 or 16.6 mM) and leucine-induced (12.5 or 25.0 mM) IRI release from isolated islets, as well as 14C02-production from U-14C glucose, were decreased. Theophylline (5.0 mM) restored the glucose sensitivity of the islets towards normal. The results indicate that tolbutamide-induced islet cell hyperplasia does not entail islet hyperfunction, as previously thought. Decreased IRI release may partially be explained by a tolbutamide-induced alteration of the adenylate cyclase/phosphodiesterase system of the B-cell.

Animals↗
PubMed1979

Effect of methylene blue and thiol oxidants on pancreatic islet GSH/GSSG ratios and tolbutamide mediated insulin release in vitro.

Methylene blue (an oxidant of NADPH), diamide (an oxidant of glutathion-SH [GSH]) and tertbutyl hydroperoxide (a substrate of glutathione peroxidase) significantly decreased the GSH content of pancreatic rat islets and decreased their GSH/GSSG ratio. They also significantly depressed the single peak insulin response to tolbutamide by the isolated perfused pancreas as well as its synergistic action with glucose in isolated pancreatic islets. These results suggest that the effect of tolbutamide alone and its synergistic action with glucose could depend on the islet NADPH and GSH. In addition it appears that augmentation of tolbutamide action by glucose in insulin release is mediated by the provision of additional NADPH and GSH through glucose metabolism.

Animals↗
PubMed1977

Stimulation of drug metabolism by rifampicin in patients with cirrhosis or cholestasis measured by increased hexobarbital and tolbutamide clearance.

Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggests that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.

Adult↗
PubMed1975

Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance.

Five healthy volunteers took 1.2 g rifampicin daily for 8 days, and before and afterwards each received hexobarbital (7.32 mg/kg) and tolbutamide (20 mg/kg) by i.v. infusion on two consecutive days. The plasma concentrations of the two drugs were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 325 to 122 min and of tolbutamide from 418 to 183 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased about three-fold and that of tolbutamide more than two-fold. Significant changes in the distribution kinetics of the two drugs were not observed. The results suggest that rifampicin is capable of inducing drug metabolism in man, which leads to an increased rate of elimination of drugs that undergo biotransformation in the liver.

Adult↗