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PubMed1999

The tolbutamide site of SUR1 and a mechanism for its functional coupling to K(ATP) channel closure.

Micromolar concentrations of tolbutamide will inhibit (SUR1/K(IR)6. 2)(4) channels in pancreatic beta-cells, but not (SUR2A/K(IR)6.2)(4) channels in cardiomyocytes. Inhibition does not require Mg(2+) or nucleotides and is enhanced by intracellular nucleotides. Using chimeras between SUR1 and SUR2A, we show that transmembrane domains 12-17 (TMD12-17) are required for high-affinity tolbutamide inhibition of K(ATP) channels. Deletions demonstrate involvement of the cytoplasmic N-terminus of K(IR)6.2 in coupling sulfonylurea-binding with SUR1 to the stabilization of an interburst closed configuration of the channel. The increased efficacy of tolbutamide by nucleotides results from an impairment of their stimulatory action on SUR1 which unmasks their inhibitory effects. The mechanism of inhibition of beta-cell K(ATP) channels by sulfonylureas during treatment of non-insulin-dependent diabetes mellitus thus involves two components, drug-binding and conformational changes within SUR1 which are coupled to the pore subunit through its N-terminus and the disruption of nucleotide-dependent stimulatory effects of the regulatory subunit on the pore. These findings uncover a molecular basis for an inhibitory influence of SUR1, an ATP-binding cassette (ABC) protein, on K(IR)6.2, a ion channel subunit.

ATP-Binding Cassette Transporters↗
PubMed1998

Assessment of microsomal tolbutamide hydroxylation by a simple thin-layer chromatography radioactivity assay.

A radio thin-layer chromatographic method is described for in vitro measurement of tolbutamide methylhydroxylation as an alternative to the commonly used HPLC assay. After the incubation experiments of [14C]tolbutamide with human liver microsomes, the supernatants were directly spotted onto standard silica gel TLC plates and developed in a horizontal chamber using a solvent system consisting of toluene-acetone-formic acid (60:39:1, v/v). Dried TLC plates were exposed to a phosphor imager plate and quantificated by use of a phosphor imager. Reaction rates were calculated from the ratio of labelled metabolite to the total radioactivity. The correlation coefficient between HPLC and the TLC method was 0.978 (n=14). The described method provides a valuable tool for the determination of tolbutamide hydroxylation activity in human liver microsomes.

Chromatography, High Pressure Liquid↗
PubMed1996

Influence of the presence of trace amounts of metals on the polymorphism of tolbutamide.

The polymorphism phenomenon causes an important problem in the preparation of many pharmaceutical dosage forms, including oral suspensions, tablets, creams and suppositories. In this work the influence of the presence of certain metallic elements (Ca(II), Fe(III), Mn(II), Zn(II), Cd(II), Ni(II) and Co(II)) in trace amounts on the polymorphism of tolbutamide is described. For these studies, known amounts (5-500 ppm) of different cations were added to ethanol-water solutions of the pharmacologically active polymorph A of tolbutamide prior to its crystallization. These cations were chosen as being among those that commonly appear in drug solutions as a consequence of elution from glass containers. IR studies show that the presence of cations prevents the appearance of the polymorph B of the tolbutamide. Thus, the peaks at 2980, 2940, 2890, 905, 851, 816 and 727 cm-1 (polymorph A) appeared but not the ones at 1045 and 847 cm-1 corresponding to polymorph B. Scanning electron microscopy studies reveal that, in the presence of Ca2+, a third kind of crystal different from polymorphs A and B appears. This form of olbutamide cannot be identified with "polymorph III" of Al-Saieq and Rileys [S.S. Al-Saieq and G.S. Riley, Pharm. Acta. Helv., 56 (1981) 125-129] due to their different IR data. Dissolution rate tests and X-ray diffractometry were also employed in this study. All these results showed that divalent cations partially avoid the transformation of polymorph A into polymorph B.

Cadmium↗
PubMed1999

Solid-state 13C nuclear magnetic resonance spectroscopic study on amorphous solid complexes of tolbutamide with 2-hydroxypropyl-alpha- and -beta-cyclodextrins.

PURPOSE: The objective of the study was to obtain structural information of inclusion complexes of tolbutamide with HP-alpha- and -beta-cyclodextrins in amorphous state. METHOD: The solid complexes of tolbutamide with HP-alpha- and -beta-CyDs in molar ratios of 1:1 and 1:2 (guest:host) were prepared by the spray-drying method, and their interactions were investigated by solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The solid 1:1 and 1:2 tolbutamide/HP-CyD complexes showed halo pattern on the powder X-ray diffractogram and no thermal change in DSC curves, indicating they are in an amorphous state. 13C NMR signals of the butyl moiety were broader than those of the phenyl moiety in the HP-alpha-CyD solid complex, whereas the phenyl moiety showed significantly broader signals than the butyl moiety in the HP-beta-CyD solid complex. As temperature increased, signals of the phenyl carbons became markedly sharper, whereas the butyl carbons only sharpen slightly in the HP-d-CyD complex. In contrast, signals of the butyl carbons became significantly sharper whereas those of phenyl carbons only slightly changed in the HP-beta-CyD complex. CONCLUSIONS: Solid state 13C NMR spectroscopic studies indicated that the butyl moiety of tolbutamide is predominantly included in the HP-alpha-CyD cavity, whereas the phenyl moiety in the HP-beta-CyD cavity in amorphous complexes.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1989

The inotropic action of tolbutamide and glyburide.

The effect of glyburide on myocardial function in human beings is not known. We divided 37 normal male volunteers into five groups. Each group received either intravenous saline solution; 10 mg propranolol by intravenous push followed by 0.1 mg/min; 5 micrograms/kg/min dobutamine; 1000 mg or 1250 mg oral tolbutamide; or 5 mg glyburide. Comparable therapeutic blood levels were obtained. Myocardial function was assessed by measurement of work product (WP, systolic pressure times heart rate) and ejection fraction (EF) by means of radionucleotide ventriculography. There was no change in EF or WP after administration of saline solution and tolbutamide; propranolol decreased EF and WP; dobutamine and glyburide increased EF and WP. In summary, tolbutamide had no effect on myocardial contractility, whereas glyburide increased myocardial contractility as measured by ejection fraction.

Administration, Oral↗
PubMed1999

Glucose and tolbutamide trigger transients of Ca2+ in single pancreatic beta-cells exposed to tetraethylammonium.

Isolated pancreatic beta-cells respond to glucose stimulation with increase of the cytoplasmic Ca2+ concentration ([Ca2+]i) in terms of membrane-derived slow oscillations (0.2-0.5/min) with superimposed transient of intracellular origin. To evaluate under which conditions transients may result also from entry of extracellular Ca2+, the cytoplasmic concentration of the ion was measured with dual wavelength fluorometry and fura-2 in individual mouse beta-cells exposed to the K+ channel blocker tetraethylammonium (TEA). In the presence of 20 mM TEA, the beta-cells responded to closure of the KATP channels (increase of the glucose concentration to 11 mM or addition of 1 mM tolbutamide) with pronounced transients of [Ca2+]i. However, there were no transients when the beta-cells were depolarized by raising extracellular K+ to 30 mM in the presence of 20 mM TEA. The glucose-induced [Ca2+]i transients became more pronounced after thapsigargin inhibition of the endoplasmic reticulum Ca(2+)-ATPase. The tolbutamide-induced transients were amplified when promoting the entry of Ca2+ (rise of extracellular Ca2+ to 10 mM or addition of BAY K 8644), unaffected in the presence of thapsigargin and the Na+ channel blocker tetrodotoxin and slightly reduced by glucagon. Blockage of voltage-dependent Ca2+ channels with methoxyverapamil resulted in a prompt disappearance of the transients induced by glucose or tolbutamide. The observations indicate that closure of the KATP channels can precipitate pronounced transients of [Ca2+]i when other K+ conductances are suppressed.

Animals↗
PubMed1975

[Pancytopenia in diabetes mellitus treatment with tolbutamide?].

Pancytopenia developed in a 72-year-old woman after three years of tolbutamide treatment. When tolbutamide was discontinued and the usual treatment of pancytopenia undertaken, the anaemia persisted while the leukopenia and thrombocytopenia were reversed. Pancytopenia during tolbutamide treatment is extremely rare. But the blood picture and platelet count should be regularly checked in all patients receiving sulphonylurea drugs, ten days after starting treatment, every three months for the first year and then once yearly.

Aged↗
PubMed2005

No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract.

We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.

Adult↗
PubMed1989

Differential regulation of two distinct glucose transporter species expressed in 3T3-L1 adipocytes: effect of chronic insulin and tolbutamide treatment.

The HepG2-type glucose transporter (HepG2-GT) is expressed in 3T3-L1 fibroblasts and adipocytes. In contrast, the acutely insulin-regulatable glucose transporter (IRGT) is expressed only in the adipocytes. In the present study, the expression of the IRGT was shown to increase in parallel with the acquisition of acutely insulin-stimulated glucose uptake during differentiation of these cells, whereas the level of the HepG2-GT decreased during the course of differentiation in parallel with a decline in basal glucose uptake. We examined the effects of chronic insulin and tolbutamide treatment on glucose transporter activity in conjunction with the expression of these two glucose transporter species in 3T3-L1 adipocytes. Treatment of adipocytes with insulin, tolbutamide, or both agents in combination increased 2-deoxyglucose uptake, HepG2-GT protein, and HepG2-GT mRNA levels in parallel. The effect of combined insulin/tolbutamide administration on these three parameters was greater than the effect of either treatment alone. In contrast, these treatments either had no significant effect or decreased levels of IRGT protein and mRNA. We conclude that chronic treatment of 3T3-L1 adipocytes with insulin or tolbutamide increases glucose uptake primarily by means of a selective increase in the expression of the HepG2-GT. We suggest that part of the in vivo hypoglycemic effect of insulin and sulfonylureas may involve an increased expression of the HepG2-GT.

Adipose Tissue↗
PubMed1984

Hypoglycaemia due to azapropazone-tolbutamide interaction.

We report a case of hypoglycaemia due to a 'first-dose' interaction between azapropazone and tolbutamide. The mechanism was probably by displacement of tolbutamide from protein binding sites, and it is recommended that azapropazone should be avoided in patients receiving tolbutamide.

Apazone↗
PubMed1997

Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation activities in livers of Japanese and Caucasian populations.

Genomic DNA was isolated from livers of 39 Japanese and 45 Caucasians and the genotypes of CYP2C9 and 2C19 genes were determined with PCR methods using synthetic oligonucleotide primers. Liver microsomes were also prepared from these human samples and activities for tolbutamide methyl hydroxylation and S-mephenytoin 4'-hydroxylation were determined. The single base mutation of C416T (Arg144Cys) in CYP2C9 was detected in 22% of Caucasians but not in Japanese samples. Another single base mutation at A1061C (Ile359Leu) in the CYP2C9 gene was found with frequencies of about 8% in both races. We did not detect any individuals who have either homozygous Cys144/Cys144 or Leu359/Leu359 CYP2C9 variant nor both heterozygous Cys144-Ile359 and Arg144-Leu359 CYP2C9 variant in the human samples examined. The CYP2C19m2 genetic polymorphism was found only in Japanese people, while CYP2C19m1 type was determined in both races, with higher incidence in Japanese than in Caucasian population. Immunoblotting analysis of human liver microsomes suggested that CYP2C9 is a major component of the human CYP2C enzyme pool; it accounted for approximately 20% of total P450 in liver microsomes of both human populations. The levels of CYP2C19 protein were determined to be about 0.8% and 1.4% of total P450 (mean) in Japanese and Caucasians, respectively. We did not detect CYP2C19 protein in liver microsomes of humans who were genotyped for CYP2C19 gene as m1/m1, m1/m2, and m2/m2 variants but detected CYP2C9 protein in all of the samples examined. Good correlations were found between levels of CYP2C9 and activities of tolbutamide methyl hydroxylation (r = 0.77) and between levels of CYP2C19 and activities of S-mephenytoin 4'-hydroxylation (r = 0.86) in liver microsomes of the human samples examined. Tolbutamide methyl hydroxylation activities were lower in human samples with the Leu359 allele of CYP2C9 than those with the Cys144 allele and wild-type (Arg144-Ile359); the former type showed slightly higher K(m) values. When calculated on P450 basis, liver microsomes of individuals having m1/m1, m1/m2, and m2/m2 types of CYP2C19 had very low catalytic activities for S-mephenytoin 4'-hydroxylation. These results provide useful comparisons for pharmacokinetic and toxicokinetic models of some of the clinically used drugs that are oxidized by CYP2C proteins in humans.

Aryl Hydrocarbon Hydroxylases↗
PubMed1987

Specificity of the inhibitory effect of dextropropoxyphene on oxidative drug metabolism in man: effects on theophylline and tolbutamide disposition.

Two groups of six healthy male volunteers were studied to assess the possibility of an interaction between dextropropoxyphene and theophylline or tolbutamide using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly or tolbutamide 500 mg i.v. with and without dextropropoxyphene hydrochloride 65 mg 8 hourly. Theophylline 8-hydroxylation was reduced by a mean of 17% but there were no changes in theophylline 1-demethylation, theophylline 3-demethylation or tolbutamide hydroxylation.

Adult↗
PubMed1989

Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro.

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 microM (tolbutamide hydroxylase), 1.9 microM (ethinyloestradiol 2-hydroxylase), 2.0 microM (cyclosporin N-demethylase), 2.1 microM (cyclosporin hydroxylase) and 25 microM (ethoxycoumarin O-deethylase). At 50 microM terbinafine concentration, inhibition was less than 5% for tolbutamide and ethoxycoumarin, approximately 12% for both cyclosporin pathways and 35% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.

Antifungal Agents↗
PubMed1994

Interaction between tolbutamide and ketoconazole in healthy subjects.

A possible interaction between tolbutamide and ketoconazole was studied in seven healthy volunteers. Treatment for 1 week with 200 mg oral ketoconazole increased the elimination half-life (from mean +/- s.d. 3.7 +/- 0.4 to 12.3 +/- 1.9 h) and AUC(0.12 h) of tolbutamide (from 309 +/- 27 to 546 +/- 20 micrograms ml-1 h) by 25 +/- 64 and 66 +/- 15%, respectively. The percentage blood glucose reduction was also increased when tolbutamide and ketoconazole were coadministered.

Administration, Oral↗
PubMed1989

Rise of plasma t-PA fibrinolytic activity in a group of maturity onset diabetic patients shifted from a first generation (tolbutamide) to a second generation sulphonylurea (gliclazide).

During treatment with tolbutamide 10 maturity onset diabetic patients had no detectable activity of tissue-type plasminogen activator (t-PA) determined on two occasions 3 months apart. All 10 patients responded on the change in treatment to gliclazide with an increase in activity of t-PA. However, after 12 months of treatment the t-PA activity in one of the 10 patients returned to the baseline level, whereas the remaining nine patients had a sustained increased t-PA activity compared to the period during treatment with tolbutamide. The concentration in plasma of t-PA antigen under basal conditions and after stimulation (venous occlusion) increased significantly during the period of treatment with gliclazide. The plasma concentrations of plasminogen activator inhibitor remained unchanged throughout the study. In contrast to these findings seven patients with marked activities of t-PA during treatment with tolbutamide retained unchanged levels of the variables reported above after a change in treatment to gliclazide. Serum glucose, HBA1c, apolipoproteins A and B, and triglycerides remained constant throughout the study, whereas serum cholesterol showed a decrease in both groups of patients after 3 months (P less than 0.05) as well as after 12 months (P less than 0.05) of treatment with gliclazide. There was no significant relationship between serum cholesterol concentrations and plasma concentrations of t-PA antigen indicating that the increase in t-PA antigen was independent of the metabolic state of the patients.

Aged↗
PubMed2004

Modeling the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide determined in sandwich-cultured rat hepatocytes.

An alternative approach is introduced in determining the in vitro intrinsic clearance of slowly metabolized compounds. The longterm sandwich rat hepatocyte culture was exploited, allowing for sufficient substrate depletion to obtain a reliable clearance estimation; in its physiology, it resembles the in vivo liver, thus allowing in vivo extrapolation of the in vitro clearance value. Substrate depletion of tolbutamide and the formation of its metabolites hydroxytolbutamide and carboxytolbutamide were measured in the medium and sandwich layer. Depletion data from the medium were fitted to a mathematical model incorporating system-dependent parameters (diffusion, protein binding, and partitioning) to calculate the hepatocytes' intrinsic clearance. Based on the decrease of the parent compound in the medium, a specific intrinsic clearance value, i.e., clearance per unit of volume of hepatocytes, of 0.085 min(-1) was fitted. This value was in accordance with in vivo and in vitro values from the literature. The model was verified with substrate depletion data from the sandwich layer. Data on metabolite formation showed an incomplete mass balance. A radiochemical experiment revealed the presence of three additional metabolites. These metabolites were analyzed by liquid chromatography-mass spectometry. One was identified as p-tolysulfonylurea. The structure of the other two needs to be elucidated. After the addition of these compounds to the metabolic pattern, the mass balance was completed. The in vitro clearance value was incorporated in a physiologically based pharmacokinetic literature model of tolbutamide that accurately describes the plasma concentration. The approach used in this study successfully predicts the intrinsic clearance of tolbutamide. In addition, the sandwich rat hepatocyte culture also proves to be useful in the identification of metabolic pathways.

Animals↗
PubMed1987

Effect of tolbutamide treatment on the pharmacokinetics of intravenously administered sulphamethoxazole in rabbits.

Fifteen days of tolbutamide treatment significantly decreased the elimination half life (t1/2), area under the curve (AUC0----infinity) and increased the clearance of sulphamethoxazole (SMZ) in rabbits. No significant difference was observed in the volume of distribution. The percentage of plasma protein binding to SMZ was not altered, while N-acetyltransferase activity in liver and kidney was significantly increased after tolbutamide therapy. The changes observed in the pharmacokinetic parameters of SMZ after tolbutamide treatment is due to the induction of liver N-acetyltransferase activity.

Animals↗
PubMed1980

Effects of tolbutamide and glyburide on glucose and acetate incorporation into aortic lipids of the dog.

The use of oral hypoglycemic agents to treat adult-onset diabetes has been implicated in an increased incidence of cardiovascular mortality. Since it is likely that altered arterial wall metabolism plays an important role in the atherogenic process and in cardiovascular disease, the primary aim of the present study was to investigate the in vitro effects of two oral hypoglycemic agents (tolbutamide and glyburide) on glucose and acetate incorporation into aortic lipids of the dog. Tolbutamide resulted in a significantly increased incorporation of glucose in total lipids, phospholipids and fatty acids of aorta, but had no apparent effect on acetate incorporation into aortic lipids. In contrast, glyburide significantly decreased glucose incorporation into the total lipid, phospholipid and triglyceride fractions. Acetate incorporation into the triglyceride, free cholesterol, fatty acid and cholesterol ester fractions of aorta also was significantly decreased by glyburide. The data indicate that the oral hypoglycemic agents tolbutamide and glyburide can alter glucose and acetate utilization by arterial tissue. These observations on arterial lipid metabolism provide sufficient justification for further studies directed towards characterizing the effects of oral hypoglycemic agents on the various aspects of arterial wall metabolism.

Acetates↗