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PubMed1997

6-Hydroxy dopamine lesions block a tolbutamide-sensitive K+ conductance in the guinea-pig substantia nigra.

A population of neurons in the anterior substantia nigra pars compacta of the guinea-pig display an outward K+ conductance, which can be activated by a brief period of hypoxia, and blocked in a dose-dependent manner by tolbutamide (100-500 microns): these features are those of an ATP-sensitive K+ channel (KATP). Typically hyperpolarisation of the cell is accompanied by a mean decrease in input resistance (IR) of 41.29 +/- 3.69 M omega (SEM), a mean decrease in resting membrane potential (RMP) of 8.58 +/- 2.41 mV and a cessation of action potential generation. These cells do not show positive immunoreactivity for tyrosine hydroxylase (TH), but they are present in slices that contain TH and release dopamine (DA). Given the intimacy of these cells with nigral DA systems, and given the fact that they have D2 receptors and respond to dopaminergic (DAergic) agents, it was of interest to see if lesions of DAergic neurons had any effect on the above response. The neurotoxin 6-hydroxy dopamine (6-OHDA) was injected into the median forebrain bundle to destroy the DAergic neurons of the nigrostriatal pathway. Unilateral lesion of this pathway produced a significant reduction in the above conductance, in the lesioned substantia nigra pars compacta (SNpc) (mean IR decrease of only 17.99 +/- 4.44 M omega (and a mean RMP decrease of 1.40 +/- 1.76 mV), whilst the hypoxia induced change in potential on the non-lesioned side was still marked and indistinguishable from that in control animals. The KATP channel would therefore appear to be under the influence of the DAergic neurons of the SNpc.

Animals↗
PubMed1989

Simple high-performance liquid chromatographic method for the determination of tolbutamide and its metabolites in human plasma and urine using photodiode-array detection.

A high-performance liquid chromatographic method has been developed for the determination of tolbutamide and its metabolites in human plasma and urine. The compounds examined were extracted with diethyl ether from the acidified biological fluid. Chlorpropamide was used as internal standard, and 235 nm was chosen as the wavelength for diode-array detection. A study of the relationship between the capacity factor and the mobile phase composition and pH showed that acetonitrile-2-propanol-0.1% orthophosphoric acid (17: 17: 66, v/v) was the best eluent on a C8 reversed-phase column. The method is precise, sensitive and suitable for pharmacological investigations.

Chromatography, High Pressure Liquid↗
PubMed2001

Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin.

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Characterization of tolbutamide polymorphs (Burger's forms II and IV) and polymorphic transition behavior.

Burger's two polymorphs of tolbutamide (TB), an oral hypoglycemic agent, were obtained by spray-drying the drug dissolved in a mixed solvent of ethanol/dichloromethane (Form IV) and allowing Form IV to stand at constant temperatures and humidities (Form II). These polymorphs were characterized by various physical methods [e.g., powder X-ray diffractometry, differential scanning calorimetry, infrared spectrometry, and solid-state carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy] and compared with two other TB polymorphs Forms I and III. The 13C NMR spectra showed that the chemical shift and the peak shape of resonance associated with the toluene and n-butyl moieties of TB were different for each of the four polymorphs, whereas the carbonyl carbon was unchanged, indicating different conformations and molecular motions of the toluene and n-butyl moieties in the solid states. Form IV converted itself to Form II within 3 h when it was stored at 45 degrees C and 75% relative humidity (RH) and, in turn, Form II transformed to Form I at higher temperatures. The conversion of Form IV to Form II proceeded according to a zero-order equation (Polany-Winger equation), and that of Form II to Form I according to a first-order equation. The increase in RH accelerated the polymorphic transition of Form IV. Both the apparent dissolution rate and the solubility of Form IV were nearly identical with those of Form II, because the former changed to the latter during the dissolution, but their dissolution rates and solubility were higher than those of Forms I and III. These dissolution characteristics of TB polymorphs were reflected in the oral absorption behavior in dogs; that is, the bioavailability increased in the order Form I < Form III < Form II approximately Form IV.

Animals↗
PubMed1999

Identification of S-(n-butylcarbamoyl)glutathione, a reactive carbamoylating metabolite of tolbutamide in the rat, and evaluation of its inhibitory effects on glutathione reductase in vitro.

Tolbutamide (TOLB), a widely used hypoglycemic agent in the therapy of non-insulin-dependent diabetes mellitus, has been reported to be teratogenic and/or embryotoxic in several animal species and humans. It has been proposed that the teratogenic effects of TOLB are linked to drug-mediated depletion of glutathione (GSH) through inhibition of the enzyme glutathione reductase (GR), although the mechanism by which this inhibition occurs remains unknown. In the study presented here, rats were injected with TOLB (200 mg/kg ip), and bile was collected for analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS). This led to the identification of S-(n-butylcarbamoyl)glutathione (SBuG), a reactive GSH conjugate derived from n-butyl isocyanate, as a minor metabolite of TOLB in bile. Upon incubation of SBuG (0.25-1.0 mM) with GR from either yeast or bovine intestinal mucosa in the presence of NADPH (0.20 mM), enzyme activity was lost in a time- and concentration-dependent manner. No inhibition was observed when NADPH was omitted from incubations, or when the natural substrate for the enzyme, glutathione disulfide (GSSG, 0.05 mM), was added. TOLB itself did not inhibit GR over the concentration range of 0.8-2.0 mM. It is concluded that metabolic activation of TOLB in vivo leads to the generation of reactive intermediates (n-butyl isocyanate and SBuG) which carbamoylate and thereby inhibit GR. At critical periods of organogenesis, the resulting perturbation of GSH homeostasis in exposed tissues may play a key role in the teratogenic and/or embryotoxic effects of TOLB.

Animals↗
PubMed2000

Deformation behaviors of tolbutamide, hydroxypropyl-beta-cyclodextrin, and their dispersions.

PURPOSE: The deformation behaviors of compressed freeze-dried and spray-dried tolbutamide/hydroxypropyl-beta-cyclodextrin molecular dispersions were evaluated and compared with similarly prepared tolbutamides (TBM), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) and as their physical dispersions. METHODS: TBM, HP-beta-CD, and their 1:1 molecular dispersions were prepared by freeze-drying and spray-drying, and physical dispersions of TBM and HP-beta-CD were blended. Deformation properties of the prepared materials were evaluated by using a compaction simulator and constants derived from Heckel plots. Molecular dynamics (MD) simulations were performed in order to gain a molecular-level view on the deformation behavior of TBM-HP-beta-CD inclusion complex. RESULTS: The freeze-dried TBM polymorphic form II was less prone to overall particle deformation than the spray-dried stable form I. Formation of molecular dispersions decreased the plastic and elastic behaviors of these materials. Also, the MD simulations showed a reduced molecular flexibility of the TBM-HP-beta-CD inclusion complex, as compared to HP-beta-CD. CONCLUSIONS: The formation of TBM and HP-beta-CD molecular dispersion resulted in more rigid molecular arrangements, which were less prone to deformation than either HP-beta-CDs or physical dispersions. The results showed how differing molecular, solid, particle, and powder state properties affect the deformation properties of the materials studied.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1969

Islet-cell metabolism during insulin release. Effects of glucose, citrate, octanoate, tolbutamide, glucagon and theophylline.

1. Concentrations of glucose 6-phosphate and 6-phosphogluconate were studied in islets of Langerhans isolated from rat pancreas and incubated in the presence of various agents that induce insulin release. 2. In response to rising concentrations of extracellular glucose (2-10mm) there is a linear increase in the intracellular concentration of glucose 6-phosphate, though this is not the case for 6-phosphogluconate, the intracellular concentration of which only increases when the external glucose concentration exceeds 5mm. 3. Tolbutamide, octanoate and citrate, all of which promote insulin secretion from isolated islets, increase the intracellular concentrations of glucose 6-phosphate and 6-phosphogluconate. The results obtained in the presence of octanoate and citrate are compatible with an inhibitory effect of citrate on islet-cell phosphofructokinase. 4. Theophylline and glucagon when incubated with islets in vitro promote insulin release and cause a rise in 6-phosphogluconate concentration and not in that of glucose 6-phosphate. 5. It is suggested that the further metabolism of glucose 6-phosphate through a pathway other than glycolysis is essential for insulin release. One such pathway involves its oxidation to 6-phosphogluconate, which seems to be a necessary accompaniment of insulin secretion due to glucose. The possibility that agents other than glucose promote insulin release by enhancing the oxidation of glucose 6-phosphate through this pathway is discussed.

Animals↗
PubMed1974

Insulin release from the perfused rat pancreas. Mode of action of tolbutamide.

Dextran-linked tolbutamide causes first-phase insulin release when perfused through the isolated rat pancreas. The linked sulphonylurea is also able to stimulate the membranal adenylate cyclase present in mouse islets. These facts make it highly likely that sulphonylureas exert their pharmacological action by interaction with the plasma membrane. Their action may be mediated via the adenylate cyclase enzyme.

Adenosine Triphosphate↗
PubMed2003

Leptin fully suppresses acetylcholine-induced insulin secretion and is reversed by tolbutamide in isolated perfused chicken pancreas.

So far, there has been no evidence for any direct pancreatic effect of leptin in the chicken. The present study was aimed at detecting chicken leptin receptor (cOb-R) expression in isolated chicken islets of Langerhans and to examine the direct effect of leptin on insulin secretion after stimulation by acetylcholine (1 micro M) + glucose (14 mM) from isolated perfused chicken pancreas. We will show that i) full length cOb-R mRNA was expressed in isolated pancreatic islets of chickens, ii) recombinant chicken leptin (10 nM) or diazoxide (100 micro M) rapidly (within 2 min) and significantly suppressed insulin secretion induced by acetylcholine stimulation without any change in volume outflow rate, iii) tolbutamide (100 micro M) introduced 10 min after leptin and perfused for 10 min fully reversed the suppressive effect of leptin on pre-established acetylcholine-induced insulin release. In conclusion, we found that leptin has a profound inhibitory influence upon insulin secretion in perfused chicken pancreas. The results suggest that leptin inhibits insulin secretion by acting before or at the level of K ATP channels in chicken pancreatic beta-cells. Further studies are warranted to clarify the specific inhibitory mechanism.

Acetylcholine↗
PubMedDate not supplied

Turner's syndrome and carbohydrate metabolism. I. Impaired insulin secretion after tolbutamide and glucagon stimulation tests: evidence of insulin deficiency.

Tolbutamide (25 mg/kg: maximum 1 mg) intravenously (IV) and glucagon (0.03 mg/kg; maximum 1 mg) intramuscularly (IM) were given sequentially to 12 untreated girls with XO-Turner's syndrome (ages 6.5 to 17.0 years) and to ten female siblings (ages 8.0 to 16.7 years) to evaluate blood sugar (BS), plasma free fatty acids (FFA), serum immunoreactive insulin (IRI), and growth hormone (IRGH) responses to these insulinogenic secretagogues in order to appreciate any differences of genotypes on carbohydrate metabolism within identical family backgrounds. Seven of 12 patients with Turner's syndrome (58%) but none of the siblings were 20% or more overweight for height. There was a family history of diabetes mellitus in 7 to 12 patients (58%). The results showed significant elevations of mean FFA levels and decreased mean IRI responses to both insulinogenic stimuli without differences in mean BS or serum IRGH responses in the Turner's syndrome patients when compared to the controls. Three of 12 patients (25%) had abnormally elevated and prolonged blood sugar responses to IM glucagon. These findings show a significant incidence of abnormal carbohydrate and lipid metabolism and insulin deficiency in untreated patients with XO-Turner's syndrome when compared to normal female siblings and implicate this chromosomal defect in the impaired insulin secretion.

Adolescent↗
PubMed1979

Insulin in portal, hepatic and peripheral venous blood after glucose, tolbutamide and glipizide stimulation. Indication of insulin release from peripheral tissues.

Insulin in portal, hepatic and/or peripheral venous blood was determined in 16 patients admitted to a surgical ward for various diseases. Portal venous blood was obtained via a catheter introduced into the portal vein either through the umbilical vein remnant or transhepatically. Four subjects were given a peroral load of glucose, followed after 60 min by i.v. tolbutamide. In simultaneous blood samples, two of these subjects showed higher insulin concentrations in peripheral venous blood than in portal venous blood. Twelve subjects were given i.v. glipizide. In one subject blood samples were drawn from the portal vein, a hepatic vein and a peripheral vein and in six subjects from the portal vein and a hepatic vein. Two subjects showed higher insulin concentrations in peripheral venous blood than in portal venous blood. The mean peripheral insulin response (six subjects) was of the same magnitude as the mean hepatic insulin response (six subjects). It is suggested that these findings reflect a release of previously bound insulin from peripheral tissues.

Adult↗
PubMed1987

Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants.

The dissolution rate of a poorly water-soluble drug, tolbutamide, was improved by spray-drying a diluted ammonia solution of the drug containing either a low-substituted hydroxypropylcellulose (L-HPC) or partly pregelatinized corn starch (PCS) as disintegrants. With L-HPC the resultant particles were agglomerates of disintegrant with drug on the surface and within the particles, while particles formed with PCS were composed of a single core of PCS on which the drug was deposited. The deposited drug crystals were very fine because the rapid solvent evaporation restricted crystal growth. The spray-dried particles prepared with PCS had a structure similar to that of an ordered mix. The drug dissolution rate from the spray-dried particles was more rapid than that of the powdered drug alone or with disintegrant and could be attributed to separation of the layer of fine drug crystals from the surface of the particles by swelling of disintegrant. PCS enhanced the drug dissolution rate compared with systems using corn starch. The dissolution rate also depended on the drug content of the particles which was higher than that in ordered mixtures or conventional solvent deposition systems. This system described also had the advantage of avoiding the use of organic solvents.

Chemical Phenomena↗
PubMed1975

Inhibition of catecholamine release by tolbutamide and other sulfonylureas.

Tolbutamide and other sulfonylureas inhibited spontaneous and nicotine-induced release of catecholamines from the perfused cat adrenal gland and nicotine-induced release of [3-H]norepinephrine from isolated guinea pig hearts. Of the sulfonylureas tested, the order to potency of this inhibitory effect paralled the hypoglycemic action. These results raise the possibility that the inhibition of the sympathoadrenal system may contribute in part to the hypoglycemic action of sulfonylureas.

Adrenal Glands↗
PubMed1979

Early insulin and glucagon response to subsequent pulses of arginine, glucose, and tolbutamide in normal man.

To determine the dynamics of insulin and of glucagon secretion in response to several sequential stimuli administered shortly after an arginine pulse (5 g), 20 nonobese, apparently healthy volunteers were given arginine (5 g), glucose (5 g), and tolbutamide (1 g) by rapid intravenous injection. The early insulin and glucagon area 0-8 min was studied. At the intervals and with the dosages used in this study, different stimuli with and without prestimulation with arginine did not lead to changes in early secretion of insulin. There was no exhaustion of the pool of insulin released after multiple sequential pulses. These results suggest a pattern in which stimulation induces a rapid release of insulin and activates the interchange between the stored and labile insulin pool; the 8-min interval is sufficient for the rapid return of the two compartments to a state of equilibrium. Also for glucagon, subsequent different stimuli did not exhaust glucagon release; nevertheless, glucagon is immediately suppressed by a submaximal glucose pulse.

Adolescent↗
PubMed1975

Adrenal response to tolbutamide-induced hypoglycemia in high altitude dwellers.

Adrenal response to tolbutamide-induced hypoglycemia was studied in 23 normal men born and living at high altitude (Morococha, Perú, 4,540 m) and compared to 23 men born and living near sea level. Fasting blood sugar was significantly lower in the high altitude dwellers (HAD) and this difference persisted throughout the test period. The blood glucose decrement at 30 min was significantly less in the HAD. Plasma cortisol response was significantly higher at 30 and 60 min in the HAD. Peak cortisol level occurred earlier in the HAD than in men living at sea level. The absolute cortisol increment at 30 min was significantly greater in the HAD.

Adrenal Glands↗
PubMed1983

Five cases of somatostatinoma: clinical heterogeneity and diagnostic usefulness of basal and tolbutamide-induced hypersomatostatinemia.

Five cases of somatostatinoma are reported, four being primarily located in the pancreas and one in the duodenum. The diagnosis was based upon the histological and immunochemical characteristics of tumoral and metastatic tissue. A marked clinical heterogeneity was noted: one patient presented with gallstones, steatorrhea, and diabetes, two patients suffered from severe hypoglycemic attacks, and two cases were admitted for obstructive jaundice. This varying symptomatology was related to differences in the circulating levels of biologically active somatostatin and to a variable cellular composition of the tumor. In all cases, a basal and/or tolbutamide-induced hypersomatostatinemia was measured. It is concluded that the clinical and hormonal features of the earlier defined somatostatinoma syndrome are no requisite for the diagnosis of somatostatinoma; the analysis of plasma somatostatin immunoreactivity might lead to a higher detection rate of this endocrine tumor.

Adenoma, Islet Cell↗
PubMed1997

The use of tolbutamide-induced hypoglycemia to examine the intraislet role of insulin in mediating glucagon release in normal humans.

Disruption of intraislet mechanisms could account for the impaired glucagon response to hypoglycemia in type 1 diabetes. However, in contrast to animals, there is conflicting evidence that such mechanisms operate in humans. We have used i.v. tolbutamide (T) (1.7 g bolus + 130 mg/h infusion) to create high portal insulin concentrations and compared this with equivalent hypoglycemia using an i.v. insulin infusion (I) (30 mU/m2 x min). Ten normal subjects underwent two hypoglycemic clamps; mean glucose; I (53 +/- 1 mg/dL); and T (53 +/- 1 mg/dL) (2.9 +/- 0.04 mmol/L vs. 2.9 +/- 0.05 mmol/L), held for 30 min. During hypoglycemia, mean peripheral insulin levels were greater with I (59 +/- 4 mU/L) than T (18 +/- 3 mU/L), P < 0.001. Calculated peak portal insulin concentrations were greater during T (282 +/- 28 mU/L) than I (78 +/- 4 mU/L), P < 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 +/- 8 ng/L vs. 135 +/- 12 ng/L, P < 0.05) with higher portal insulin concentrations suggests that intraislet mechanisms may contribute to the release of glucagon during hypoglycemia in man.

Adult↗
PubMed1994

Pharmacokinetics of tolbutamide following intravenous and oral administrations in rats with obstructive jaundice.

The pharmacokinetics of tolbutamide (TB) following intravenous and oral administration was compared between normal rats and rats with experimentally-induced obstructive jaundice (OJ). The plasma concentration-time curve of i.v. administered TB was lower in rats with OJ, in comparison with normal rats. The result of the pharmacokinetic analysis showed no change in the elimination rate constant, but a significant increase in the volume of distribution in the OJ state. The increase in the volume of distribution of TB could be explained by the decreased protein binding in plasma. In the case of oral administration, the elevation of the plasma concentration was slow and the plasma concentration profile was remarkably low in rats with OJ. The rate of TB disappearance from the small-intestinal lumen was delayed in the OJ state, and its marked accumulation in the tissues of the small intestine and the liver was observed. This retarded uptake by the small-intestinal mucosa and subsequent pre-systemic accumulation might, at least in part, be the reason for the slow appearance in the systemic plasma in the OJ state.

Administration, Oral↗