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PubMed1979

Pharmacogenetics of tolbutamide metabolism in humans.

This study was designed to focus on the genetic control of tolbutamide dispositon in humans and to provide insight into the potential for high accrued blood levels in individuals receiving fixed dosage regimens. Tolbutamide was administered intravenously to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins. A ninefold variation in the rate of tolbutamide disappearance from plasms (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate. Interindividual differences in the binding of 35S-tolbutamide to serum proteins were also assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control. In conclusion, this study provides evidence for monogenic control of tolbutamide metabolism in man. The results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.

Adolescent↗
PubMed1982

Effect of chronic tolbutamide administration on normal and obese-hyperglycemic mice: evidence for post-receptor potentiation of insulin action.

Obese-hyperglycemic mice (genotype ob/ob) have hyperglycemia, hyperinsulinemia, increased resistance to insulin action and decreased insulin receptors on their liver, fat cell and muscle plasma membranes. Hypoglycemic sulfonylureas are reported to improve diabetic control by decreasing the insulin resistance of subjects with Type II diabetes mellitus: however, it is not clear if their mechanism is to increase plasma membrane insulin receptors or to decrease post-receptor insulin resistance. In this study we treated obese-hyperglycemic mice and their normal weight litter mates with the oral hypoglycemic sulfonylurea tolbutamide for 28 to 34 weeks. Tolbutamide administration to normal mice resulted in the following changes that were indicative of increased insulin action: (1) increased body weight; (2) increased epididymal fat-pad weight; (3) increased 2-deoxyglucose transport into the intact diaphragm muscle preparation. There was no alteration in plasma glucose, plasma insulin or pancreatic insulin content suggesting that the tolbutamide effect was an extrapancreatic effect that was probably not mediated by increased insulin secretion. There was no change in the insulin receptor number or affinity of liver cell membranes prepared from tolbutamide treated mice supporting the notion that the extrapancreatic effect of tolbutamide may occur at a post-insulin receptor location. In contrast to the normal mice, tolbutamide did not increase the body weight, epididymal fat pad weight, the already increased 2-deoxyglucose transport into diaphragm muscle or the decreased number of insulin receptors on hepatic plasma membranes. The tolbutamide caused a striking decrease in pancreatic insulin concentration and degranulation of the islets in obese but not normal mice. This is compatible with previous information that the obese mice have abnormal islets that are not under the normal feed-back control of ambient insulin concentration as are the islets of normal mice. We conclude that tolbutamide potentiates insulin action in normal, but not obese, mice and that this potentiation may be due to a post-insulin receptor action.

Animals↗
PubMed1977

On the question of an interaction between sulindac and tolbutamide in the control of diabetes.

The effect of sulindac and tolbutamide on the control of diabetes was studied in 12 tolbutamide-treated maturity-onset diabetics with stable glycemic control. After one week of hospitalization on a metabolic ward for adjustment of diet and activity, the patients were treated with sulindac, 200 mg twice daily for one week. The time-to-peak plasma tolbutamide concentration was 3.1, 3.1, and 3.2 hr, respectively, after tolbutamide alone, after the first dose of sulindac, and after sulindac for a week. The areas under the plasma tolbutamide curve were 23.68, 22.10, and 22.78 for the same periods. The half-life for plasma tolbutamide was 7.46, 7.15, and 7.38 hr, respectively. None of the differences were statistically significant. The mean fasting plasma sugar was lower after the sulindac treatment (from 12.5 to 112.9 mg/100 ml, p less than 0.05), but the postprandial values increased slightly (from 137.7 to 142.6). It was concluded that there was no clinically significant interaction between sulindac and tolbutamide.

Adult↗
PubMed2006

Tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation.

Our previous work has shown that tolbutamide increases gap junctional permeability in poorly coupled C6 glioma cells and that this effect is similar and additive to that found with dbcAMP, a well-known activator of gap junctional communication. Furthermore, the increase in gap junctional communication promoted by tolbutamide or dbcAMP is concurrent with the inhibition of proliferation of C6 glioma cells. In the present work, we show that tolbutamide and dbcAMP increase the synthesis of the tumor suppressor protein Cx43 and that they decrease the level of Ki-67, a protein expressed when cells are proliferating. These effects were accompanied by a reduction in the phosphorylation of pRb, mainly on Ser-795, a residue critical for the control of cell proliferation. The decrease in the phosphorylation of pRb is not likely to be mediated by a reduction in the levels of D-type cyclins, since instead of decreasing the expression of cyclins, D1 and D3 increased slightly after treatment with tolbutamide or dbcAMP. However, the Cdk inhibitors p21 and p27 were up-regulated after treatment with tolbutamide and dbcAMP, suggesting that they would be involved in the decrease in pRb phosphorylation. When Cx43 was silenced by siRNA, neither tolbutamide nor dbcAMP were able to up-regulate p21 and consequently to reduce glioma cell proliferation, as judged by Ki-67 expression. In conclusion, tolbutamide and dbcAMP inhibit C6-glioma cell proliferation by increasing Cx43, which correlates with a reduction in pRb phosphorylation due to the up-regulation of the Cdk inhibitors p21 and p27.

Animals↗
PubMed1990

Tolbutamide-sensitivity of the adenosine 5'-triphosphate-dependent K+ channel in mouse pancreatic B-cells.

The patch-clamp technique was used to examine the tolbutamide-sensitivity of the adenosine 5'-triphosphate (ATP)-dependent K+ channel in mouse pancreatic B-cells. When studied at 37 degrees C in cell-attached membrane patches, this channel had a single-channel conductance of 88 pS and was half-maximally inhibited by 2.2 mumol/l tolbutamide in the presence of 3 mmol/l D-glucose and 10 mumol/l nifedipine. The tolbutamide-induced decrease in the amplitude of the single-channel currents indicated that the membrane potential was sufficiently depolarized for initiation of insulin release by 30 but not by 10 mumol/l of tolbutamide. Using 300 mumol/l diazoxide to open the ATP-dependent K+ channels already closed by 3 mmol/l D-glucose alone, it was demonstrated that initiation of insulin release requires closure of more than 98% of all ATP-dependent K+ channels. In excised inside-out membrane patches, the K+ channel-blocking potency of tolbutamide was maximally enhanced by 0.3 mmol/l adenosine 5'-diphosphate (ADP) at the cytoplasmic side. This ADP effect required the presence of Mg2+. Inhibition of K+ channel activity by ATP, ADP (Mg2(+)-free) or their non-hydrolyzable analogues adenylyl-imidodiphosphate (AMP-PNP) and alpha, beta methylene adenosine 5'-diphosphate (AMP-CP) was not accompanied by enhancement of tolbutamide-sensitivity. The results suggest that cytosolic MgADP controls tolbutamide-sensitivity by interaction with a receptor site not identical with the site mediating channel closure and that this control plays a role in the intact B-cell.

Action Potentials↗
PubMed1982

The effect of food on the bioavailability and pharmacodynamics of tolbutamide in diabetic patients.

The effect of food on the rate and extent of absorption of tolbutamide in diabetic patients was studied by varying the time of drug administration in relation to the ingestion of a standard meal. Serum levels of tolbutamide, insulin and glucose and related bioavailability parameters were compared following the administration of a single dose of tolbutamide 0.5 g to diabetic patients 30 min prior to and immediately before a standardized meal. A placebo dosage form was also administered to determine baseline glucose and insulin response to the meal. The 700 calorie standard meal was composed of 41% carbohydrate, 18% protein, and 41% fat. Administration of the drug with the meal resulted in a 6% (statistically significant) decrease in the extent of absorption, as determined by measurement of the area under the tolbutamide serum level-time curve from zero to infinity. Serum levels of tolbutamide were also significantly higher 0.5 h after drug administration when the drug was taken with the meal. Except for these two minor effects, no other differences between the drug treatments were observed in any other parameters of tolbutamide absorption or in the postprandial glucose and insulin serum levels. Therefore, the small differences found were judged to be clinically meaningless. These findings demonstrate that administration of tolbutamide 0.5 g tablets 30 min prior to or with a standard meal results in equivalent therapeutic actions.

Adult↗
PubMed1986

Lack of inhibition of tolbutamide hydroxylation by cimetidine in man.

We have investigated the influence of cimetidine on the disposition of tolbutamide in 7 healthy subjects, who received 250 mg tolbutamide daily for 4 days followed by the concomitant intake of cimetidine 400 mg twice daily for a further 4 days. Cimetidine had no effect on the disposition of tolbutamide, including the unbound hydroxylation clearance rate (324 ml X min-1, tolbutamide alone; 316 ml X min-1, tolbutamide plus cimetidine). The total urinary recovery of carboxy- and hydroxy-tolbutamide metabolites was 85.7 +/- 20.3% of the dose when tolbutamide was given alone and 78.9 +/- 14.3% when given with cimetidine. This lack of a pharmacokinetic interaction suggests selectivity of cimetidine-induced inhibition of Phase I drug oxidation.

Adult↗
PubMed1987

Interaction of diazoxide, tolbutamide and ATP4- on nucleotide-dependent K+ channels in an insulin-secreting cell line.

The single-channel current recording technique has been used to study the effects of diazoxide, tolbutamide and ATP, separately and combined, on the gating of nucleotide-regulated K+ channels in the insulin-secreting cell line RINm5F. The effects of diazoxide, tolbutamide and ATP4- were studied at the intracellular membrane surface, using the open-cell membrane patch configuration. Alone diazoxide was found only inconsistently to evoke channel stimulation, 57% of all applications of the drug (72 times in 48 separate patches) having no effect at concentrations between 0.02 and 0.4 mM. In the presence of ATP, however, diazoxide consistently evoked channel activation (seen 87 times in 49 patches, 95% of all applications). The interactions of diazoxide and ATP seemed competitive. Stimulation of channels by diazoxide in the presence of 1 mM ATP was suppressed if the concentration of ATP was elevated to 2 or 5 mM. In solutions in which Mg2+ had been chelated with EDTA, diazoxide failed to activate channels closed by 1 mM ATP; however, this was not due to a direct effect on the channels caused by the absence of Mg2+, but could be explained by the enhanced ATP4- concentration after Mg2+ removal. When the total ATP concentration was lowered to give the same [ATP4-] in the absence of Mg2+ to that present in the control experiments, diazoxide was able to evoke full activation. Channel inhibition evoked by tolbutamide, 0.01 to 1.0 mM, did not require the presence of either ATP or Mg2+. In the presence of ATP tolbutamide further reduced the number of channel openings. Diazoxide was able to compete with tolbutamide for control of channel activity, an effect that was augmented by the presence of ATP. In the presence of 0.1 mM tolbutamide, diazoxide was unable to stimulate channel openings; however, if the dose of tolbutamide was lowered or ATP made available to the inside of the membrane, channel stimulation occurred.

Adenosine Triphosphate↗
PubMed1988

Tolbutamide hydroxylation by human liver microsomes. Kinetic characterisation and relationship to other cytochrome P-450 dependent xenobiotic oxidations.

Tolbutamide hydroxylation has been investigated in human liver microsomes. Anti-human liver NADPH-cytochrome P-450 reductase IgG inhibited hydroxytolbutamide formation and this metabolite was not formed when NADPH-generating system was omitted from microsomal incubations. Tolbutamide hydroxylation followed Michaelis-Menten kinetics, consistent with the involvement of a single form of cytochrome P-450 in this reaction. Mean apparent Km and Vmax values for hydroxytolbutamide formation were 120 +/- 41 microM and 0.273 +/- 0.066 nmol min-1 mg-1, respectively. A range of clinically used drugs and xenobiotics used as probes for cytochrome P-450 activity in laboratory animals was screened for inhibitory effects on hydroxytolbutamide formation. Caffeine, paraxanthine, theophylline, theobromine, debrisoquine, erythromycin, phenacetin, propranolol, aminopyrine, benzo(a)pyrene and 7-ethoxycoumarin were all found not to inhibit tolbutamide hydroxylation. In contrast, sulphaphenazole, phenylbutazone, nifedipine, verapamil, cimetidine, aniline, dextropropoxyphene and mephenytoin were competitive inhibitors of tolbutamide hydroxylation. The respective apparent Ki values for these compounds were 0.12 microM, 11 microM, 15 microM, 118 microM, 140 microM, 182 microM, 225 microM and 375 microM. Sulphinpyrazone inhibited tolbutamide hydroxylation with atypical kinetics. The in vitro data is in good agreement with in vivo drug interactions with tolbutamide. The data also confirm that tolbutamide hydroxylation is not associated with the cytochromes P-450 responsible for methylxanthine metabolism or with the form responsible for the polymorphic oxidation of debrisoquine.

Cytochrome P-450 Enzyme System↗
PubMed1992

Effect of tolbutamide and glyburide on pyruvate kinase flux in isolated rat hepatocytes.

The effects of two representative sulfonylureas, tolbutamide and glyburide, on pyruvate kinase (PK) flux were examined in fasted rat hepatocytes. PK flux was estimated by trapping 14C from NaH14CO3 in a 2 mM lactate pool, accounting for any incomplete trapping by parallel incubations with L-[1-14C]alanine. Glyburide (20 microM) and tolbutamide (1 mM) decreased glucose formation by 34.9% and 54.8%, respectively, from 2 mM lactate. This decrease in glucose formation was associated with a proportional decrease in pyruvate carboxylase (PCOX) flux (32.7% and 50.5%, respectively). Under these conditions, no net change in PK flux was observed. When hepatocytes were preincubated with lactate and/or sulfonylurea addition for 30 min prior to radiolabeling with NaH14CO3, the metabolic state of the cells changed markedly. Glyburide produced a 34.6% decrease in glucose formation and a 31.3% decrease in PCOX flux, but no change in PK flux. In contrast, tolbutamide decreased glucose formation by 12.5% and increased PK flux by 53.2%, but no change in PCOX flux was observed. Such an increase in PK flux may be linked to tolbutamide-mediated increases in fructose-1,6-bisphosphate (F16P) via fructose-2,6-bisphosphate (F26P). These findings demonstrate that tolbutamide and glyburide decrease hepatic glucose production through various alterations in carbohydrate metabolism, depending upon the metabolic state of the cell. In addition, F26P may play a larger role in the hypoglycemic mechanism of action of tolbutamide than glyburide, since pyruvate carboxylase accounted for most of the decrease in glucose formation observed with glyburide and because preincubation with tolbutamide resulted in an activation of PK.

Animals↗
PubMed2006

Polysaccharide peptides from COV-1 strain of Coriolus versicolor inhibit tolbutamide 4-hydroxylation in the rat in vitro and in vivo.

Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy in China. In this study, the effects of whole PSP extract and water extract of PSP on 4-hydroxylation of tolbutamide were investigated in rat liver microsomes in vitro and in vivo in the rat. Both the whole PSP extract and the water soluble fraction (0.5-20 microM) decreased the metabolism of tolbutamide to 4-hydroxytolbutamide in vitro. Enzyme kinetics studies showed that PSP inhibited tolbutamide 4-hydroxylase activity in a competitive, concentration-dependent manner. The whole PSP extract had a Ki value of 12.6 microM and IC50 at 18.4 microM, while the water extract had a Ki value of 6.9 microM and IC50 at 9.8 microM. Sulphaphenazole, a specific human CYP2C9 inhibitor, showed a Ki value of 30.8 microM and IC50 at 44.0 microM in the test system. In the pharmacokinetic studies in vivo, acute PSP (4 micromol/kg, i.p.) treatment did not produce significant changes in tolbutamide clearance, but produced a decrease in the Cinitial (7.4%) and an increase in the Vd (7.4%). Sub-chronic pre-treatment of PSP (1-2 micromol/kg/day, i.p.) for three days did not affect the clearance and AUC of tolbutamide, but the Cinitial was decreased, together with increases in the T1/2, and Vd. The formation of 4-hydroxytolbutamide in vivo was decreased in both acute and sub-chronic studies. Taken together, this study demonstrated the PSP can inhibit tolbutamide 4-hydroxylation both in vitro and in vivo. Despite the fact that CYP isoforms that metabolise tolbutamide are different between rat and human liver due to different catalytic characteristics, and rat studies may not be directly extrapolatable to man, the concomitant use of PSP with other CYP2C substrates should be carefully monitored.

Animals↗
PubMed2001

Persistent hypoglycemia is induced by tolbutamide administration in broiler chickens fed a low-carbohydrate diet.

With a view to gaining an insight into the regulatory mechanism of blood glucose concentrations specific to the chicken, an experimental induction of hypoglycemia was conducted by single or sequential administration of tolbutamide in broiler chickens fed a standard or low-carbohydrate diet. A single dosing of tolbutamide at levels of 25-200 mg/kg body weight decreased plasma glucose concentrations for 2 to 8 h after the dosing in chickens fed either diet. No significant rise in plasma insulin concentration was observed for 2 to 24 h after the single dosing of tolbutamide in chickens on either diet, with the exception of a significant rise when chickens on the standard diet received 100 mg tolbutamide. However, a transient increase of plasma insulin concentration was observed only in the 20 min immediately after the single dosing. Persistent hypoglycemia that was sustained for 5 days, with no significant changes in plasma insulin concentration, was induced by sequential dosing (3 times per day for 5 days, every 8 h) of tolbutamide (100 and 200 mg/kg body weight) in chickens fed the low-carbohydrate diet. In these chickens, the consistently low concentration of plasma glucose, with small diurnal variations, was evidenced by the determination of plasma glucose every 3 h in day 4/5 of the tolbutamide dosing. In chickens fed the standard diet, on the other hand, the low plasma glucose concentrations for 5 days were accompanied by significant diurnal fluctuations. Chickens with persistent hypoglycemia showed slight decreases in plasma non-esterified fatty acids (NEFA) concentration and only slight changes in blood D-3-hydroxybutyrate (3HB) concentration. The present study shows that the persistent hypoglycemia with normoinsulinemia, in the main, is induced by tolbutamide dosing in chickens fed a low-carbohydrate diet, and that the blood concentrations of NEFA and 3HB, alternatives of energy source in animals, are only slightly changed or not at all in hypoglycemic chickens.

Animals↗
PubMed2002

Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C91 heterozygotes.

OBJECTIVES: Multiple single-nucleotide polymorphisms in the gene encoding cytochrome P450 (CYP) 2C9 have been identified, but the functional significance of the various putative defective genotypes in humans merits further study. METHODS: Using tolbutamide as a probe of CYP2C9 activity, we evaluated CYP2C9 phenotype in 15 healthy individuals expressing the CYP2C9(*)1/(*)1, (*)1/(*)2, and (*)1/(*)3 genotypes (n = 5 per group). CYP2C9 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism methods. Subjects received 500 mg of tolbutamide, with plasma and urine collected over a 24-hour period. Plasma tolbutamide and urinary tolbutamide, 4'-hydroxytolbutamide, and carboxytolbutamide concentrations were determined by an HPLC method. RESULTS: Tolbutamide area under the plasma concentration-time curve from time zero to infinity [AUC(0- infinity )] significantly increased by 1.5-fold and 1.9-fold, respectively, in subjects expressing the CYP2C9(*)1/(*)2 and (*)1/(*)3 genotypes compared with (*)1/(*)1 subjects. Statistically significant reductions in tolbutamide oral clearance (29% and 48%) and formation clearance (38% and 56%) were detected in the (*)1/(*)2 and (*)1/(*)3 individuals, respectively, compared with (*)1/(*)1 subjects. The increases in AUC(0- infinity) and decreases in oral clearance observed in the (*)1/(*)3 individuals were also significantly greater than those expressing the (*)1/(*)2 genotype (P <.05). The amount of urinary 4'-hydroxytolbutamide and carboxytolbutamide excreted in the 0- to 12-hour and 6- to 12-hour collection intervals was significantly less in (*)1/(*)2 and (*)1/(*)3 individuals compared with (*)1/(*)1 subjects. With tolbutamide used as a CYP2C9 probe, CYP2C9 genotype was the major determinant of CYP2C9 phenotype (r(2) = 0.77). CONCLUSIONS: CYP2C9 activity was significantly reduced in (*)1 heterozygotes compared with (*)1 homozygotes, and metabolism was more severely impaired in (*)1/(*)3 individuals compared with those expressing (*)1/(*)2.

Adolescent↗
PubMed1993

Tolbutamide hydroxylation in humans: lack of bimodality in 106 healthy subjects.

The tolbutamide hydroxylation capacity was studied in 106 healthy unrelated volunteers from the Australian population. Following a 500 mg oral dose of tolbutamide, the ratio of metabolites (hydroxytolbutamide plus carboxytolbutamide) to unchanged tolbutamide excreted in urine from 6 to 12 h post-dose (urinary metabolic ratio, MR) was determined. Metabolic ratio values did not appear bimodally distributed, even following various transformations of the data (i.e. Log10, inverse, Log10 inverse). A poor metabolizer (PM) subject from a previous clinical study, however, could be distinguished (MR value 159) from the above subjects (MR value range 324-3033), particularly from the histogram plot of inverse tolbutamide metabolic ratio. The poor metabolizer's parents had metabolic ratio values (526 and 478) that were at the lower end of the range of metabolic ratios obtained from the population study, and may indicate that they both have a heterozygous genotype and that a recessive form of inheritance is most likely. As the hydroxylations of tolbutamide and phenytoin are closely linked, the incidence of slow tolbutamide metabolizers is likely to be similar to that for phenytoin (about 1:500) and this is consistent with the failure to detect a single poor tolbutamide metabolizer in our random sample of 106 individuals.

Adolescent↗
PubMed1987

Tolbutamide 4-hydroxylase activity of human liver microsomes: effect of inhibitors.

Eight samples of human liver have been characterised for microsomal protein content, cytochrome P-450 content, tolbutamide 4-hydroxylase and ethinyloestradiol 2-hydroxylase activities. Cytochrome P-450 content correlated significantly with ethinyloestradiol 2-hydroxylase activity but not with tolbutamide 4-hydroxylase activity. There was no significant correlation between ethinyloestradiol 2-hydroxylase and tolbutamide 4-hydroxylase activities. The maximum tolbutamide 4-hydroxylase activity was 0.45 nmol min-1 mg-1 microsomal protein, with a Km value of 74 microM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non-competitive or mixed non-competitive inhibitors of tolbutamide 4-hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P-450 which appears to be distinct from those isozymes metabolising many other drugs.

Adolescent↗
PubMed1994

Interaction of tolbutamide and cytosolic nucleotides in controlling the ATP-sensitive K+ channel in mouse beta-cells.

1. In mouse pancreatic beta-cells the role of cytosolic nucleotides in the regulation of the sulphonylurea sensitivity of the adenosine 5'-triphosphate-sensitive K+ channel (KATP-channel) was examined. Patch-clamp experiments with excised inside-out membrane patches were carried out using an experimental protocol favouring phosphorylation of membrane proteins. 2. In the absence of Mg2+, the KATP-channel-inhibiting potency of cytosolic nucleotides decreased in the order ATP = adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) > adenosine 5'-diphosphate (ADP) > adenosine 5'-O-(2-thiodiphosphate) (ADP beta S) = adenylyl-imidodiphosphate (AMP-PNP) > 2'-deoxyadenosine 5'-triphosphate (dATP) > uridine 5'-triphosphate (UTP) > 2'-deoxyadenosine 5'-diphosphate (dADP) > guanosine 5'-triphosphate (GTP) > guanosine 5'-diphosphate (GDP) > uridine 5'-diphosphate (UDP). 3. In the presence of Mg2+, the inhibitory potency of cytosolic nucleotides decreased in the order ATP gamma S > ATP > AMP-PNP > ADP beta S > dATP > UTP. In the presence of Mg2+, the KATP-channels were activated by dADP, GTP, GDP and UDP. 4. Tolbutamide inhibited the KATP-channels not only in the presence but also in the prolonged absence of Mg2+. In nucleotide-free solutions, the potency of tolbutamide was very low. When about half of the KATP-channel activity was inhibited by ATP, AMP-PNP, ADP beta S or ADP (absence of Mg2+), the potency of tolbutamide was increased. 5. Tolbutamide (100 microM) slightly enhanced the channel-inhibiting potency of AMP-PNP and inhibited the channel-activating effect of MgGDP in a non-competitive manner. 6. Channel activation by MgGDP (0.5 mM) competitively antagonized the inhibitory responses to AMP-PNP (1 MicroM- 1 mM). This effect of GDP was neutralized by tolbutamide (100 MicroM).7. The stimulatory effect of 0.5 mM MgGDP was neutralized by 200 MicroM AMP-PNP. Under these conditions the potency of tolbutamide was much higher than in the presence of 0.5 mM MgGDP alone or in the absence of any nucleotides.8. dADP (0.3-1 mM) increased the potency of tolbutamide. Additional application of 200 MicroM AMPPNP caused a further increase in the potency of tolbutamide.9. In conclusion, in the simultaneous presence of inhibitory and stimulatory nucleotides, binding of sulphonylureas to their receptor causes direct inhibition of channel activity, non-competitive inhibition of the action of stimulatory nucleotides and interruption of the competitive interaction between stimulatory and inhibitory nucleotides. The latter effect increases the proportion of KATP- channels staying in the nucleotide-blocked state. In addition, this state potentiates the direct effect of sulphonylureas.

Adenine Nucleotides↗
PubMed1999

A Chinese traditional medicine, sho-saiko-to (xiao-chaihu-tang), reduces the bioavailability of tolbutamide after oral administration in rats.

The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were investigated in rats. After intravenous administration of tolbutamide (5 mg/kg), no significant change in the pharmacokinetics of tolbutamide was observed in both groups of single and multiple (7 days) pre-administration of Sho-saiko-to (500 mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co-administration of Sho-saiko-to tended to accelerate the initial absorption rate of tolbutamide. The area under the plasma concentration-time curve of tolbutamide after oral administration was significantly reduced by Sho-saiko-to. Subsequently, a significant decrease was observed in the oral bioavailability of this drug when Sho-saiko-to was given concomitantly. These findings suggest that Sho-saiko-to reduces the bioavailability of tolbutamide after oral administration in rats, and that this change is not related to hepatic metabolism.

Algorithms↗
PubMed1995

Tolbutamide inhibits glucagon-induced phosphorylation of 6PF-2-K/Fru-2,6-P2ase in rat hepatocytes.

In previous studies, we demonstrated that tolbutamide inhibits a phosphorylation of hepatic 6-phosphofructo-2-kinase (6PF-2-K)/fructose-2,6-bisphosphatase (Fru-2,6-P2ase) catalyzed by the adenosine 3',5'-cyclic monophosphate-dependent protein kinase in a reconstruction system using the purified enzyme from the rat liver. In the current study, to assess a role of tolbutamide on hepatic 6PF-2-K/Fru-2,6-P2ase physiologically, we used intact rat hepatocytes and examined effects of tolbutamide on a phosphorylation of the bifunctional enzyme in the presence of glucagon. Glucagon induced a rapid phosphorylation of hepatic 6PF-2-K/Fru-2,6-P2ase accompanied by an inhibition of 6PF-2-K activity and a stimulation of Fru-2,6-P2ase activity in a dose-dependent manner. Tolbutamide inhibited glucagon-induced phosphorylation of the bifunctional enzyme protein in a dose-dependent manner. By adding 2 mM tolbutamide, reduced activity of 6PF-2-K and increased activity of Fru-2,6-P2ase in the presence of 10(-9) M glucagon were partially restored. The present results suggest the possibility that tolbutamide modulates the activity of hepatic 6PF-2-K/Fru-2,6-P2ase through inhibiting a phosphorylation of the enzyme protein. The counterregulatory influence of tolbutamide on the effect of glucagon suggests a possible mechanism for the extrapancreatic effect of sulfonylurea drugs.

Animals↗