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PubMed1964

EFFECT OF DOSAGE FORM PROPERTIES ON THERAPEUTIC EFFICACY OF TOLBUTAMIDE TABLETS.

The rate of gastrointestinal absorption and the physiologic availability of tolbutamide are functions of the dissolution rate of the drug in gastrointestinal fluids. This property can be modified markedly by pharmaceutical formulation factors. The in vitro dissolution rates of clinically efficacious and clinically inefficacious tolbutamide tablets have been determined, and it has been found that the former dissolved considerably more rapidly than the latter. Once diabetic patients have been "titrated" with a particular brand of tolbutamide they should not be switched to a different brand without "retitration." There is need to establish an adequate in vitro test to assure the physiologic availability of tolbutamide from commercial tablets.

Absorption↗
PubMed1999

Cromakalim: embryonic effects and reduction of tolbutamide-induced dysmorphogenesis in vitro.

Cromakalim is a K(+) channel opener that causes smooth muscle relaxation by activating ATP-sensitive K(+) (K(ATP)) channels and producing membrane hyperpolarization. Cromakalim counteracts sulfonylurea-induced K(ATP) channel inhibition in adult cells, but little is known regarding its embryonic effects, alone or in combination with sulfonylureas. K(ATP) channels have been demonstrated in the embryo, but their role in normal and abnormal development is unknown. Early-somite mouse embryos were exposed for 24 hr in vitro to cromakalim at concentrations of 0 (Cntl), 1, 10, 100, 200, or 500 microM in 0.125% DMSO. Embryos were also exposed for 24 hr in vitro to a dysmorphogenic tolbutamide concentration (110 microg/ml) combined with a subdysmorphogenic concentration of cromakalim (1 microM). Embryos were evaluated for somite number, heart rate, malformations, and embryonic and yolk sac protein content. Embryos exposed to 1 microM cromakalim were similar to controls. Cromakalim exposure increased malformation rates at concentrations >/=200 microM, decreased heart rates at >/=10 microM, and decreased somite and protein values at 500 microM. Defects involved cranial neural tube, optic vesicle, heart, and somites. A malformation rate of 59% in embryos exposed to 110 microg/ml tolbutamide was reduced to 13% by adding 1 microM cromakalim to the culture medium. Heart rate, somite number, and protein values were also improved by combined exposure to cromakalim and tolbutamide compared with exposure to tolbutamide alone. These results support previous findings with diazoxide (K(+) channel opener) and chlorpropamide (sulfonylurea) and further suggest a potential role for K(ATP) channel effects in sulfonylurea-induced dysmorphogenesis.

Abnormalities, Multiple↗
PubMed1976

Plasma protein binding of diazepam and tolbutamide in chronic alcoholics.

The increased incidence of drowsiness in hypoalbuminemic patients administered diazepam and more rapid clearance of tolbutamide in cirrhotics may be due to changes in plasma protein binding. The binding of diazepam and tolbutamide was studied by equilibrium dialysis at 37degreesC over a total drug concentration range of 1 to 10 mug/ml and 50 to 300 mug/ml, respectively, in plasma from 21 normal and 14 alcoholic subjects. At 1 mug/ml, diazepam plasma protein binding (+/- S.D.) was 98.5+/-0.4 per cent in normals and 97.8+/-1.2 per cent in alcoholics; at 100 mug/ml, tolbutamide binding was 97.8+/-0.3 per cent in normals and 95.1+/-4.2 per cent in alcoholics. For both agents at all concentrations, the binding to plasma from alcoholics was significantly decreased (P less than 0.01-less than 0.02). The extent of binding of both drugs was dependent on the albumin concentration. These findings suggest that important changes in pharmacologic effect, distribution, and clearance of diazepam and tolbutamide can be anticipated in alcoholics with hypoalbuminemia.

Alcoholism↗
PubMed1976

High-pressure liquid chromatographic analysis of tolbutamide in serum.

A high-pressure liquid chromatographic (HPLC) analysis of tolbutamide in serum is described. The assay requires only 1 ml of serum and is capable of measuring as little as 2 mug of tolbutamide. The metabolites of tolbutamide do not interfere in the assay. Human serum samples, taken after a 1-g oral dose of tolbutamide, were analyzed by the HPLC and an existing GLC procedure, and the results are compared.

Chromatography, Gas↗
PubMed1980

Comparison of polyethylene glycol and polyoxyethylene stearate as excipients for solid dispersion systems of griseofulvin and tolbutamide I: phase equilibria.

Phase equilibrium diagrams were constructed based on hot-stage microscopy and differential scanning calorimetry of solid dispersions of griseofulvin or tolbutamide in polyethylene glycol 2000 or polyoxyethylene 40 stearate. The solid dispersions were prepared by physical mixing, fusion, and coprecipitation from ethanol. The phase diagrams were largely independent of the method of preparation of the dispersion systems. The diagrams were of the monotectic type for polyethylene glycol 2000 with each drug and for griseofulvin with each excipient, with the monotectic species being the pure drug. Polyoxyethylene 40 stearate with tolbutamide gave eutectic systems in which liquid polyoxyethylene 40 stearate dissolved up to 20% of the tolbutamide. The phase diagrams showed greater solubility of tolbutamide in liquid polyoxyethylene 40 stearate than in polyethylene glycol 2000 but showed a similar solubility of griseofulvin in each experiment. Solid solution formation was not detected.

Excipients↗
PubMed1981

High-performance liquid chromatographic assay of tolbutamide and carboxytolbutamide in human plasma.

A high-performance liquid chromatographic method was developed for the simultaneous measurement of tolbutamide and its major metabolite, carboxytolbutamide, in plasma. The assay involves the ether extraction of 1 ml of plasma, using chlorpropamide and an internal standard. The extract is dried, the residue is taken up in acetonitrile, and 5 micro l is injected into a reversed-phase column. The mobile phase consisted of 35% acetonitrile and 65% 0.05 M phosphoric acid buffer (pH 3.9). A fixed-wavelength detector was set at 254 nm. The sensitivity limits for the tolbutamide and carboxytolbutamide assay were 2 and 0.1 microgram/ml, respectively. The ratio of carboxytolbutamide to tolbutamide in plasma obtained from a subject given a 500-mg tolbutamide tablet was 1:20.

Chlorpropamide↗
PubMed1981

Effect of pirprofen on protein binding of warfarin and tolbutamide in human plasma.

The extent of warfarin and tolbutamide binding to plasma proteins was determined with and without pirprofen by an ultrafiltration procedure employing 14C-labeled drugs. Results from in vitro studies at 37 degrees showed that the degree of binding amounted to 97.8% for warfarin and 95.6% for tolbutamide. The binding characteristics of these drugs were not altered when plasma containing either warfarin or tolbutamide at concentrations equivalent to those expected normally after therapeutic dosing were concomitantly spiked with therapeutic amounts of pirprofen. Consequently, potentiation resulting from drug displacement would not be anticipated in humans when pirprofen is administered along with warfarin or tolbutamide.

Anti-Inflammatory Agents↗
PubMed1984

Generic tolbutamide tablet dissolution: intralot and interlot variation.

Dissolution profiles for 62 lots of tolbutamide tablets from six manufacturers have been characterized using the USP paddle-stirrer apparatus. Results of paddle-stirrer dissolution for percent drug dissolved at 10, 20, and 30 min correlated well (r2 = 0.7444) with results from the USP rotating-basket test for 39 lots of tolbutamide. Interlot and intralot variability in tolbutamide dissolution was highly dependent on the manufacturer. For one product, the intralot range (for six paddle-stirred tablets) of percent drug dissolved after 30 min was 50-68% while the maximum interlot range for mean dissolution was 58-104%. One lot failed to meet both the rotating-basket and the paddle-stirrer dissolution specifications. Tablet response to aging at 60, 75, and 98% relative humidity over time was also highly manufacturer specific. The innovator's product repeatedly dissolved well when fresh or aged at all humidities. Dissolution from some generic tablets was dramatically depressed by humidity aging, even after only 3 d. Pretreatment of tablets with simulated gastric fluid modified the dissolution profile of one poorly dissolving lot of tablets. Results indicate that manufacturing quality control is highly variable among tolbutamide tablets.

Humidity↗
PubMed1993

The effect of tolbutamide on rat embryonic development in vitro.

Tolbutamide (TOLB) is a sulfonylurea used to treat non-insulin-dependent diabetes mellitus and is a suspected teratogen. However, it is not possible to discriminate between potential teratogenic effects of TOLB and malformations produced by either drug-induced hypoglycemia or the diabetic state itself. We examined the direct effect of TOLB on rat embryos cultured in a rodent whole embryo culture system. CD strain rat embryos were cultured for 48 h beginning on day 9 of gestation (plug day = day 0). Tolbutamide was added at various concentrations (90-3,600 microM). At the end of culture, viable embryos were examined for morphological score, number of somite pairs, crown-rump and head lengths, and DNA and protein content. Tolbutamide produced dose-related decreases in all endpoints at concentrations (2,250-3,600 microM) which are two to four times the human therapeutic concentration. Sera from TOLB-treated rats were adjusted to contain equal concentrations of glucose and insulin and then used for embryo culture. Serum from TOLB-treated rats had no observable effect on embryonic development. The mechanism for the embryotoxic effect of TOLB is unknown; however, the drug was previously demonstrated to alter activity of purified yeast glutathione reductase (GR). Because GR may be important for normal embryonic development, the effect of TOLB on this enzyme activity in cultured rat embryos was evaluated. Tolbutamide (2,700 microM) reduced embryonic GR activity by 35-57%. These results indicate that TOLB has a direct embryotoxic effect at levels 2 to 4 times the usual therapeutic serum concentrations on developing rodent embryos which may be mediated by GR inhibition.

Animals↗
PubMed1993

Tolbutamide inhibits gluconeogenesis in the tumor-influenced hepatocyte.

The tumor-bearing state is associated with an increase in gluconeogenesis which may contribute to the development of cancer cachexia. The purpose of this study was to determine if tolbutamide, a drug known to decrease gluconeogenesis in diabetes, could decrease gluconeogenesis in hepatocytes isolated from tumor-bearing rats. Hepatocytes from 24-hr fasted normal and methylcholanthrene-induced sarcoma-bearing rats (5-10% tumor burden) were isolated by in situ collagenase liver perfusion. Hepatocytes (n = 12 samples) from non-tumor-bearing (NTB) controls and tumor-bearing (TB) rats were incubated with lactate (10 mM) and alanine (10 mM) with and without 1 mM tolbutamide. Supernatant glucose concentration was measured at 30-min intervals for 2 hr. Rates of gluconeogenesis (+/- standard error) were calculated by linear regression and are expressed as nmole glucose/10(6) cells/min. Comparisons were made by two-way analysis of variance and significance defined as P < 0.05. TB hepatocytes had an increased rate of gluconeogenesis (P < 0.0001) from alanine and lactate (3.8 +/- 0.30 and 2.2 +/- 0.10, respectively) compared with NTB hepatocytes (0.66 +/- 0.10 and 1.2 +/- 0.04, respectively). TB hepatocytes treated with tolbutamide had a decreased (P < 0.0001) rate of gluconeogenesis from alanine and lactate (3.1 +/- 0.10 and 1.1 +/- 0.10, respectively) compared with untreated TB hepatocytes (5.3 +/- 0.10 and 2.1 +/- 0.10, respectively). Tolbutamide inhibits gluconeogenesis from lactate and alanine in tumor-influenced hepatocytes.

Alanine↗
PubMed1993

Tolbutamide-sensitive potassium conductance in the basolateral membrane of A6 cells.

K+ channels sensitive to intracellular ATP (KATP channels) have been described in a number of cell types and are selectively inhibited by sulfonylurea drugs. To look for the presence of this type of K+ channel in the basolateral membrane of tight epithelia, we have used an amphibian renal cell line, the A6 cells, grown on filters. After the selective permeabilization of the apical membrane with amphotericin B, the basolateral conductance was studied under voltage-clamp conditions. Tolbutamide inhibited 65.8 +/- 6.3% of the barium-sensitive current. The tolbutamide-sensitive conductance had an equilibrium potential of -83 +/- 1 mV and was inward rectifying in spite of the outwardly directed K+ gradient. Similar results were obtained with glibenclamide. The half-inhibition constants were 25.7 +/- 3.0 microM and 0.114 +/- 0.018 microM for tolbutamide and glibenclamide, respectively. To study the relation between cellular ATP and the activity of this conductance, A6 cells were treated with glucose (5 mM) and insulin (250 microU/ml). This maneuver significantly increased the cellular ATP and abolished the tolbutamide-sensitive conductance. A sulfonylurea-sensitive K+ conductance is present and active in the basolateral membrane of A6 cells. This conductance appears to be modulated by physiological changes of intracellular ATP.

Adenosine Triphosphate↗
PubMed1978

Characterisation of the effect of intravenous infusion of glucose and tolbutamide on the insulin delivery rate in man.

Serum insulin response to a single bolus of IV glucose or tolbutamide was measured in eight healthy subjects. Insulin disappearance rate was assessed by deconvolution from the serum insulin levels, using the measured insulin disappearance rate. The mean rate constant of insulin disappearance was 0.238 +/- 0.005 min-1 (mean +/- SEM). Basal insulin delivery rate was 8.0 to 9.0 mU/min and the delivery rate following glucose injection (0.5 g/kg body weight) showed a biphasic response, whereas that after tolbutamide injection (15.6 mg/kg body weight), a monophasic response. After glucose injection, 1.7 +/- 0.3 U of insulin was delivered during the first phase (0--10 min) and 5.6 +/- 1.6 U during the second phase (11--60 min). After tolbutamide injection, 1.5 +/- 0.3 U of insulin was delivered during the first 10 min. Between 11 and 40 min, 1.6 +/- 0.5 U of insulin was delivered. The results thus confirm and also quantitate biphasic insulin secretion after a bolus of glucose with a monophasic response after tolbutamide. The method is suitable for studies of the insulin secretogogues in man.

Glucose↗
PubMed1983

The effect of glucose, tolbutamide, and arginine on C-peptide release during remission in type I diabetes mellitus.

The insulin secretory capacity was examined in diabetic children at the time of partial clinical remission during which their condition could be managed with low insulin therapy (less than 0.5 U insulin/kg body weight) and no urinary glucose excretion. The extent of the residual beta cell function in 26 children was assessed either by an i.v. arginine test, a combined i.v. glucose-i.v. arginine test, a combined i.v. tolbutamide-i.v. arginine test, or a combined oral glucose-i.v. arginine test determining the C-peptide response by calculating the area under the curve above baseline levels. Two of the children were tested repeatedly. Under the above conditions i.v. glucose and i.v. tolbutamide did not release C-peptide in diabetic children. In contrast, C-peptide secretion during arginine infusion following i.v. glucose or i.v. tolbutamide was significantly enhanced compared to the C-peptide secretion observed during arginine infusion alone. The C-peptide response to oral glucose was sluggish with no effect on the following arginine infusion. The results indicate that during remission in juvenile onset diabetes i.v. glucose and i.v. tolbutamide without themselves being an appropriate signal for C-peptide release amplify the response to a subsequent arginine infusion under appropriate conditions.

Adolescent↗
PubMed1979

Insulin release by tolbutamide and glibenclamide. A comparative study on the perfused rat pancreas.

Glibenclamide, a "second generation" sulfonylurea, produced the same pattern of insulin release from the perfused rat pancreas as did tolbutamide. The stimulatory effect was closely dependent on the glucose concentration present. Both agents enhanced insulin secretion at 5--10 mM glucose, whereas no additional insulin was released when maximally stimulating levels of glucose (20 and 30 mM) were present. The concentrations of glibenclamide stimulating insulin release were 100--400 times lower than equieffective levels of tolbutamide. At glucose levels of 3 or 8 mM, however, glibenclamide did not liberate significantly more insulin from the pancreas than did tolbutamide. Thus the differences of tolbutamide and glibenclamide were quantitative rather than qualitative. Although the active concentrations differed the effects produced were comparable.

Animals↗
PubMed1987

Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype.

The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine. The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml.min-1.kg-1, 3.4 h, and 0.17 ml.min-1. kg-1 in PM subjects and 0.22 ml.min-1.kg-1, 4.3 h and 0.15 ml.min-1.kg-1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance. These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme. The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.

Adult↗
PubMed1994

Inhibitory effects of tryptamine on tolbutamide-induced hypoglycemia in mice: mediation by 5-HT receptors.

Effects of tryptamine on tolbutamide-induced hypoglycemia were investigated in mice. Tryptamine significantly inhibited hypoglycemia elicited by tolbutamide. The inhibitory effects of tryptamine were strongly blocked by the 5-HT1 and 5-HT2 receptor antagonist methysergide and the 5-HT2 receptor antagonist ketanserin, while the 5-HT3 receptor antagonist ICS 205-930 was without effect. Tryptamine induced hyperglucagonemia in tolbutamide-treated mice, and this effect elicited by tryptamine was strongly inhibited by the 5-HT2 receptor antagonist ketanserin. These results suggest that the inhibitory effects of tryptamine on tolbutamide-induced hypoglycemia are mediated by 5-HT2 receptors and that tryptamine is involved in glucagon release.

Animals↗
PubMed1983

Protein binding and hepatic clearance: studies with tolbutamide, a drug of low intrinsic clearance, in the isolated perfused rat liver preparation.

The influence of altered drug binding on the hepatic elimination of tolbutamide, a drug of low intrinsic clearance, and on the formation of its metabolite, hydroxytolbutamide, was examined under linear conditions at steady state in the isolated in situ single-pass perfused rat liver preparation, with perfusate flow fixed at 15 ml/min. The fraction of tulbutamide unbound in the perfusate was varied (from 0.06 to 1.0) by either varying the perfusate concentration of albumin or using albumin of different animal species. The intrinsic clearance of tolbutamide varied fourfold between preparations (0.08-0.36 ml/min/g liver). Within each preparation the data were normalized to observations with a perfusate containing no protein. Both the extraction ratio (and clearance) of tolbutamide and the fraction of tulbutamide appearing as hydroxytolbutamide in effluent perfusate, a measure of hepatic metabolism, were directly proportional to the fraction of tolbutamide unbound in the perfusate.

Animals↗
PubMed1991

Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9.

A human cytochrome P4502C9 cDNA clone has been isolated from a human liver bacteriophage Lambda gt11 library using oligonucleotide probes. Expression of the 1762 base pair cDNA in COS cells demonstrated that the encoded enzyme has a molecular mass of 55 kDa as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expressed enzyme catalysed the methylhydroxylation of tolbutamide with an apparent Km of 131.7 microM, similar to that observed in human liver microsomes. P4502C9 also catalysed the 4-hydroylation of phenytoin, and inhibition experiments demonstrated that phenytoin was a competitive inhibitor of tolbutamide hydroxylation with an apparent Ki of 19.1 microM. Sulphaphenazole was a potent inhibitor of the expressed enzyme with respect to both tolbutamide and phenytoin hydroxylations. These data demonstrate that a single isozyme can catalyse the hydroxylations of both tolbutamide and phenytoin, and suggest that both reactions are mediated by the same isozyme(s) of cytochrome P450 in human liver.

Animals↗