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PubMed2006

Micronization and polymorphic conversion of tolbutamide and barbital by rapid expansion of supercritical solutions.

Rapid expansion of supercritical solutions (RESS) was applied to tolbutamide and barbital. The solubility in supercritical CO2 was determined to estimate the extraction efficiency roughly by a simple method and accurately by a direct spectrophotometric technique. The latter revealed that the solubility of tolbutamide was a function of applied pressure and temperature and was proportional to the pressure. No significant difference in solubility between polymorphic Forms I and II of tolbutamide was detected. Tolbutamide and barbital particles produced by the RESS were characterized by size distribution measurement, polymorph identification and morphological evaluation. Significant size reduction to micron or sub-micron level with narrow size distribution was achieved, while conventional mechanical grinding had only slight effect. The particle size was greatly affected by both extraction and expansion conditions. The lower the extraction temperature was, the smaller was the mean particle size. Higher extraction pressure resulted in smaller mean particle size when compared at the same extraction temperature. The mean particle size was reduced by lowering the spray nozzle temperature, by lowering the expansion chamber temperature, by increasing the CO2 amount per spray, and by increasing the exhaust gas flow rate. The RESS processing realized the polymorphic conversion as well. As for tolbutamide, three polymorphs (Forms I, II, and IV) out of four could be produced by changing the extraction conditions, and in the case of barbital, one polymorph (Form II) out of three was produced consistently.

Barbital↗
PubMedDate not supplied

Effects of changes in external calcium concentration and frequency of stimulation on inotropic responses to isoprenaline and tolbutamide in rabbit atria.

1. Driven left atrial preparations were used to study inotropic responses to isoprenaline and tolbutamide. 2. Decreasing the external calcium concentration from 2.2 to 1.1 and 0.55 mM decreased resting force of contraction but increased the maximal inotropic responses to isoprenaline. There was an associated increase in EC50 values. 3. Decreasing the external calcium concentration from 2.2 to 1.1 mM also increased the maximal inotropic responses to tolbutamide. These responses were 23- and 44-fold less than those to isoprenaline at equivalent calcium concentrations. 4. Preparations maintained in 1.1 mM calcium were used to compare inotropic responses to isoprenaline and tolbutamide at different frequencies of stimulation. 5. Decreasing the frequency of stimulation from 4 to 2 or 1 Hz decreased the resting force of contraction and increased the maximal inotropic responses to isoprenaline. There was an associated increase in EC50 values. 6. No significant inotropic responses to tolbutamide were observed at 4 Hz. Positive inotropic responses of similar magnitude occurred at 2 and 1 Hz. The maximal inotropic responses at these frequencies were 43- and 127-fold less than those to isoprenaline. 7. It is concluded that tolbutamide is a very weak inotropic agent.

Animals↗
PubMed1988

An analysis of the haemodynamic effects of tolbutamide in conscious dogs.

1. In conscious chronically instrumented dogs, tolbutamide (5-45 mg/kg) induced significant dose-related increases in mean arterial pressure and left ventricular end-diastolic pressure. 2. Cardiac output was decreased while heart rate, d(LVP)/dt, and regional myocardial performance at the left ventricle were not significantly affected. Computed total peripheral resistance was increased. 3. Pretreatment with the alpha-antagonist phentolamine (1-1.5 mg/kg) abolished the pressor response. Furthermore, the pressor response to norepinephrine (0.1 microgram/kg) was enhanced by pretreatment with tolbutamide (45 mg/kg). 4. In an isolated tissue preparation using ring segments of canine femoral arteries, neither tolbutamide nor its major hepatic metabolites (carboxytolbutamide, p-toluene-sulfonamide and p-toluene-sulfonylurea) caused any smooth muscle contraction. However, pretreatment of these tissues with 10(-4), 10(-3), or 10(-2) mol/l tolbutamide potentiated the contractile response to norepinephrine by up to 19% and to phenylephrine by up to 8%. 5. It was concluded that the pressor effect of tolbutamide arises by potentiating the alpha-adrenoceptor mediated vasoconstrictor action of circulating endogenous catecholamines.

Adrenergic alpha-Antagonists↗
PubMed1990

Comparison of tolbutamide and metformin in elderly diabetic patients.

In a randomized double-blind cross-over study the efficacy, metabolic effects, and acceptability of metformin were compared with tolbutamide in 20 diabetic patients aged between 65 and 95 years. No significant differences were noted after treatment in blood glucose control (fasting plasma glucose, metformin 9.1 +/- 2.8 mmol l-1, tolbutamide 8.3 +/- 2.8 mmol l-1; mean change, metformin +1.1 mmol l-1, tolbutamide +0.02 mmol l-1, p = 0.215), domiciliary blood glucose control, fasting insulin, lactate, cholesterol or triglyceride levels. There was a significant difference in weight change between the two treatments (on metformin -2.0 kg, from 63.2 +/- 11.8 to 61.2 +/- 12.3; on tolbutamide, +1.6 kg, from 61.4 +/- 11.1 to 63.0 +/- 12.3; p = 0.001). Initial gastro-intestinal side-effects occurred in 30% of patients with metformin. These were transient and responded to temporary reduction in treatment dosage. Metformin could not be distinguished from tolbutamide in elderly diabetic patients, except in that it was associated with weight loss.

Aged↗
PubMed2005

Preserved insulin response to tolbutamide in hepatocyte nuclear factor-1alpha mutation carriers.

AIMS: Diabetic subjects with mutations in the gene encoding hepatocyte nuclear factor (HNF)-1alpha (MODY3) are prone to develop hypoglycaemia at low doses of glibenclamide, interpreted as sulphonylurea hypersensitivity. The present study was undertaken to compare the plasma insulin responses to glucose and tolbutamide in HNF-1alpha mutation carriers with those of healthy control subjects. METHODS: Seven mutation carriers; three normoglycaemic, two with impaired glucose tolerance, and two with newly detected diabetes, underwent an oral glucose tolerance test and a tolbutamide-modified intravenous glucose tolerance test with measurements of plasma insulin. Twenty-two healthy subjects served as controls. RESULTS: The plasma insulin response to intravenous glucose was reduced in the HNF-1alpha mutation carriers compared to the control subjects, with an area under the curve (median (interquartile range)) of 812 min pmol/l (421, 1647) and 1933 min pmol/l (1521, 2908), respectively (P = 0.03). In striking contrast, the plasma insulin response to tolbutamide was preserved, with an area under the curve of 2109 min pmol/l (1126, 3172) and 2250 min pmol/l (1614, 3276) in the mutation carriers and control subjects, respectively. CONCLUSIONS: HNF-1alpha mutation carriers are characterized by preserved tolbutamide-induced insulin secretion. Compared to healthy subjects, our MODY3 individuals did not show any increased serum insulin response to tolbutamide, suggesting that HNF-1alpha mutation carriers are not characterized by sulphonylurea hypersensitivity.

Adult↗
PubMed2006

Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats.

In this study, we investigated whether pomegranate juice could inhibit CYP2C9 activity. The ability of pomegranate juice to inhibit the diclofenac 4'-hydroxylase activity of human CYP2C9 was examined using human liver microsomes. Pomegranate juice was shown to be a potent inhibitor of human CYP2C9. The addition of 25 microl (5% v/v) of pomegranate juice resulted in almost complete inhibition of human CYP2C9 activity. In addition, we investigated the effect of pomegranate juice on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. Relative to the control group, the area under the concentration-time curve was approximately 1.2-fold greater when pomegranate juice (3 ml) was injected p.o. 1 h before the p.o. administration of the tolbutamide (20 mg/kg). The elimination half-life of tolbutamide was not altered by pomegranate juice administration. These results suggest pomegranate juice ingestion inhibits the intestinal metabolism of tolbutamide without inhibiting the hepatic metabolism in rats. Thus, we discovered that pomegranate juice inhibited human CYP2C9 activity and furthermore increased tolbutamide bioavailability in rats.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Utility of rat liver slices to estimate hepatic clearance for application in physiologically based pharmacokinetic modeling: a study with tolbutamide, a compound with low extraction efficiency.

Liver slice experiments were performed to determine the slice intrinsic clearance and to extrapolate this to the in vivo liver intrinsic clearance in a physiologically based pharmacokinetic (PBPK)-like approach. Precision-cut liver slices were incubated with different initial concentrations of tolbutamide, and the time series of parent and metabolite concentrations were measured in slice and incubation medium. A mathematical model was built that modeled the uptake of tolbutamide and its metabolism in the liver slice. In addition, binding of tolbutamide to cellular constituents and partition over the water and lipid phase were accounted for by the model. Model analysis imposed sampling of parent compound in slice and of metabolites pooled from slice and medium. The model was calibrated to the data, fitting the intrinsic clearance, the parent compounds' free fraction in liver material, and a diffusion parameter describing medium-slice exchange of tolbutamide. In addition, to ensure a meaningful application of the theoretical model, slice viability parameters were monitored before and during the experiment. For the different incubations, the intrinsic clearance per unit of volume of slice ranged from 0.035 to 0.086 min(-1) when not correcting for slice viability and from 0.044 to 0.11 min(-1) when correcting for slice viability. The results were extrapolated to a PBPK model for tolbutamide in the rat. The value for the intrinsic clearance found by calibrating the PBPK model to previous in vivo data was 0.090 min(-1). This result suggests that liver slices are a valuable tool for predicting in vivo intrinsic clearance of low-extraction compounds.

Animals↗
PubMed2005

Dual mechanism of the potentiation by glucose of insulin secretion induced by arginine and tolbutamide in mouse islets.

Glucose induces insulin secretion (IS) and also potentiates the insulin-releasing action of secretagogues such as arginine and sulfonylureas. This potentiating effect is known to be impaired in type 2 diabetic patients, but its cellular mechanisms are unclear. IS and cytosolic Ca(2+) concentration ([Ca(2+)](i)) were measured in mouse islets during perifusion with 3-15 mmol/l glucose (G3-G15, respectively) and pulse or stepwise stimulation with 1-10 mmol/l arginine or 5-250 micromol/l tolbutamide. In G3, arginine induced small increases in [Ca(2+)](i) but no IS. G7 alone only slightly increased [Ca(2+)](i) and IS but markedly potentiated arginine effects on [Ca(2+)](i), which resulted in significant IS (already at 1 mmol/l). For each arginine concentration, both responses further increased at G10 and G15, but the relative change was distinctly larger for IS than [Ca(2+)](i). At all glucose concentrations, tolbutamide dose dependently increased [Ca(2+)](i) and IS with thresholds of 25 micromol/l for [Ca(2+)](i) and 100 micromol/l for IS at G3 and of 5 micromol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on [Ca(2+)](i) increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and [Ca(2+)](i) at increasing arginine or tolbutamide concentrations became steeper as the glucose concentration was raised. Thus glucose augmented more the effect of each agent on IS than that on [Ca(2+)](i). In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of [Ca(2+)](i) and the action of Ca(2+) on exocytosis. This dual mechanism must be borne in mind to interpret the alterations of the potentiating action of glucose in type 2 diabetic patients.

Animals↗
PubMed1982

Tolbutamide enhancement of ouabain cardiotoxicity in rabbits.

The amount of ouabain necessary to produce ventricular fibrillation (VF) was significantly decreased by 2-hour pretreatment with 50, 100 or 200 mg/kg tolbutamide in anesthetized rabbits. The two higher doses also decreased the dose of ouabain needed to produce ventricular ectopic (VE) beats. Only the 200 mg/kg dose decreased blood glucose. In unanesthetized rabbits, 30-min pretreatment with tolbutamide (200 mg/kg i.v.) significantly decreased the doses of ouabain that produced VE beats and VF. A similar effect was noted when the same dose (200 mg/kg) was given subcutaneously 30 min, 2 or 4 h before ouabain. In these experiments blood glucose decreased after 1 h. Pretreatment for 30 min with subcutaneous administration of 50, 100 or 200 mg/kg tolbutamide significantly reduced the doses of ouabain needed to produce VE beats and VF. Blood glucose was unaltered by any tolbutamide dose after 30 min. Insulin (1 unit) decreased blood glucose but did not alter the amount of ouabain that produced VE beats and VF. The mechanism for enhancement of ouabain cardiotoxicity by tolbutamide appears to be independent of alterations in blood glucose and may be related to some direct myocardial effect.

Anesthesia↗
PubMed1976

The relative roles of calcium, phosphorus, and parathyroid hormone in glucose- and tolbutamide-mediated insulin release.

The relative contributions of Ca++, phosphorus, and parathyroid hormone (PTH) on insulin secretion were evaluated in three groups of dogs. Dogs were studied with glucose infusions (group I) or standard intravenous glucose tolerance tests (IVGTT) (group II) before and after the development of diet-induced hypophosphatemia. Mean serum phosphorus levels for both groups fell from 4.1 to 1.1 mg/100 ml. Animals in group I demonstrated a fall in glucose disappearance rates (Kg) from 5.3+/-0.6% min to 3.5+/-0.5% after induction of hypophosphatemia (P less than 0.001). Mean insulin response was significantly greater in the hypophosphatemic animals than in controls in this group. In group II animals, mean insulin areas obtained during the IVGTT increased from 1,426+/-223 to 2,561+/-141 muU/ml/60 min after induction of hypophosphatemia, and were unaffected by Ca++ or PTH administration. Ca++ administration, but not hypophosphatemia or PTH infusion, increased significantly the mean insulin response to tolbutamide. Secondary hyperparathyroidism was induced by dietary manipulation in four dogs (group III). Mean PTH values increased from 71.4+/-2.1 to 3,012+/-372 pg/ml (P less than 0.001). Mean insulin response to an IVGTT was similar to group III animals, but increased from 1,352+/-128 to 1,894+/-360 muU/ml/60 min after the excessive dietary phosphorus was reduced for 3 mo, and plasma phosphorus fell from 3.2+/-0.1 to 2.8+/-0.3 mg/100 ml. PTH values decreased to 647+/-53 pg/ml. The insulin response to tolbutamide was comparable to that in group II animals, but increased significantly after calcium administration. Immunoreactive insulin disappearance rates were unaffected by hypophosphatemia or diet-induced secondary hyperparathyroidism. These data demonstrate that hypophosphatemia is associated with an augmented glucose-stimulated insulin release, without any effect on tolbutamide-stimulated insulin release. Hypercalcemia produces an augmented tolbutamide-stimulated insulin release with no apparent effect on glucose-stimulated insulin release. Finally, PTH does not appear to be an insulin antagonist and has no apparent effect on either glucose- or tolbutamide-stimulated insulin release in animals with dietary-induced secondary hyperparathyroidism.

Animals↗
PubMed2000

Lack of interaction between tolcapone and tolbutamide in healthy volunteers.

To assess the effect of tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between tolcapone and tolbutamide when given together in clinical practice appear unlikely.

Administration, Oral↗
PubMed2003

Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans.

The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.

Adult↗
PubMed1979

Response of the fetal and newborn lamb to glucose and tolbutamide infusions.

Tolbutamide infused into the chronically catheterized sheep fetus produced significant secretion of insulin. An optimal dose range of 100-200 mg/kg estimated fetal weight was demonstrated. Paired tolbutamide and glucose infusions using a square wave technique demonstrated that although early phase insulin secretion is dimished in the fetus, this is not due to an absolute deficiency of stored insulin. Tolbutamide produced peak insulin concentrations of 51.6 +/- 9.0 muu/ml by 20 min postinfusion in the fetus. When similar tolbutamide infusions were performed in neonatal lambs, qualitatively similar insulin response curves were demonstrated although peak insulin levels were much greater (260 +/- 70 muu/ml at 20 min). A fall in plasma glucose was demonstrated in both fetal and neonatal lambs (to 75 and 39% of control values, respectively) by 60 min after tolbutamide infusion. In the fetus, this fall was not associated with changes in maternal glucose concentration.

Animals↗
PubMed1991

Effects of tolbutamide on growth and body composition of nondiabetic children with cystic fibrosis.

Previously, we reported that nondiabetic children with cystic fibrosis show a blunted insulin response to a meal stimulus. In the study presented here, using tolbutamide, we determined the effects of augmented insulin secretion/action on height and lean body mass of children with cystic fibrosis. Twelve subjects (mean +/- SEM age, 11.0 +/- 0.5 y) were studied for three 4-mo periods: 1) pretreatment, 2) treatment, consisting of 750 mg/d of tolbutamide, and 3) posttreatment. Before the pretreatment period, insulin response to a meal stimulus was evaluated in relation to three doses of tolbutamide: 0, 250, and 500 mg. Growth was monitored during each period, and incremental changes in lean body mass were calculated from height data. To validate the change in lean body mass based on height measurements, we determined lean body mass in seven subjects during the treatment period by using a criterion method (H218O). Growth velocity (cm/4 mo) significantly increased (p less than 0.05) during the treatment (2.58 +/- 0.31) compared with the pretreatment period (0.88 +/- 0.20). The increase in lean body mass calculated from height was greater during the treatment (1.61 +/- 0.29 kg/4 mo) than during the pretreatment period (0.44 +/- 0.18 kg/4 mo) (p less than 0.05). There was also a significant increase (p less than 0.05) in lean body mass during the treatment as measured with H218O (1.91 +/- 0.65 kg/4 mo). Acute administration of either 250 or 500 mg of tolbutamide reduced (p less than 0.05) the area under the glucose concentration curve in response to a meal compared with the control condition of no tolbutamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1980

The effect of lithium on glucose- and tolbutamide-induced insulin release and glucose tolerance in the intact rat.

The effects of lithium on stimulus-induced insulin release and glucose tolerance were examined in intact, unanesthetized, and unrestrained rats with indwelling intravascular catheters. In the first study, a 150-mg iv glucose pulse was administered at 30 min after rapid iv injection of lithium carbonate (1 meq/kg) or vehicle. After the glucose pulse, mean serum glucose levels throughout the observation period were significantly greater in the lithium-treated rats than in the vehicle-treated (control) rats. Similarly, a mean glucose disappearance rate of 2.8 +/- 0.2%/min in the lithium-treated rats was significantly less (P < 0.02) than the mean glucose disappearance rate of 3.4 +/- 0.2%/min observed in the control rats. In response to glucose pulse, acute insulin release was significantly inhibited in the lithium-treated rats compared with that observed in the control rats. In the second study, a 10-mg tolbutamide pulse was administered 30 min after a rapid iv injection of lithium carbonate or vehicle. Acute insulin release in response to tolbutamide pulse was markedly inhibited in the lithium-treated rats compared with that observed in the control rats. In lithium-treated rats, the decline in serum glucose between 10-45 min after the tolbutamide pulse was significantly less than that observed in the control rats. Therefore, in the intact rat, lithium inhibits glucose- and tolbutamide-induced insulin release, which, in turn, causes glucose intolerance and prevents tolbutamide-induced hypoglycemia.

Animals↗
PubMed1994

A new method for comparing portal and peripheral venous insulin delivery in humans: tolbutamide versus insulin infusion.

We describe a new noninvasive method for comparing insulin secreted acutely by the pancreas vs. a matched peripheral venous insulin infusion in humans. An intravenous tolbutamide infusion algorithm was developed that produced sustained steady rates of portal insulin secretion over 5 h in 11 healthy young men. Plasma glucose levels were maintained in the euglycemic range by adjusting the rate of an iv dextrose (20%) infusion. The pancreatic insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution using standard parameters for a two-compartment mathematical model for C-peptide distribution and metabolism. On a subsequent occasion in the same subject, exogenous insulin was infused peripherally at a rate that matched the earlier tolbutamide-induced pancreatic insulin secretory rate, and euglycemia was maintained with a variable 20% dextrose infusion. The assumption that tolbutamide, when used in this fashion, has no independent insulin-like or insulin-potentiating effect at either low or high levels of peripheral insulinemia, does not affect insulin clearance, and does not suppress peripheral glucagon levels was validated in four patients with insulin-dependent diabetes mellitus. Mean peripheral immunoreactive insulin was significantly higher in the insulin infusion study than in the tolbutamide study (286 +/- 31 vs. 156 +/- 21 pmol/L; P = 0.0001). The dextrose infusion rates required to maintain euglycemia were also higher in the insulin infusion study (0.44 +/- 0.03 vs. 0.32 +/- 0.03 mmol/kg.min; P = 0.003). The MCR of insulin was greater in the tolbutamide infusion vs. the exogenous insulin infusion study (32.6 +/- 2.9 vs. 19.8 +/- 2.2 mL/kg.min; P = 0.0003), probably due to the hepatic first pass effect on insulin clearance when insulin is delivered by the portal route. This noninvasive method can be used in future studies to examine the relative importance of direct hepatic vs. peripheral effects of insulin in controlling hepatic glucose and lipid production.

Adult↗
PubMed2001

Free radical-mediated tolbutamide desensitization of K+ATP channels in rat pancreatic beta-cells.

To study the effects of hydroxyl radicals on the sensitivity of the ATP-sensitive K+ (K+ ATP) channel to tolbutamide, we used patch clamp and microfluorometric techniques in pancreatic beta-cells isolated from rats. cell-attached membrane patches, exposure of the cells to 0.3 mM H2O2 increased the probability of opening of K+ATP channels in the presence of 2.8 mM glucose. Tolbutamide dose-dependently inhibited the K+ATP channel with half-maximal inhibition (IC50) at 0.8 microM before and immediately after exposure to H2O2. After prolonged exposure (>20 min) to H2O2, the IC50 was increased to 15 microM. The presence of both ATP and ADP at concentrations ranging from 0.01 to 0.1 mM in the inside-out bath solution significantly enhanced the inhibition of the channels by 10 microM tolbutamide. Addition of 0.3 mM H2O2 induced a transient minute increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) within 10 min, followed by a sustained pronounced increase in [Ca2]i. After more than 20 min of exposure of cells to 0.3mM H2O2, [Ca2]i was increased to above 2 microM. Treatment of the cytoplasmic face of inside-out membrane patches with 1 microM Ca2+ attenuated the tolbutamide-sensitivity of the K+ATP channel, but not the ATP-sensitivity of the channel. These findings indicate that H2O2 reduces tolbutamide sensitivity by inducing a sustained increase in [Ca2+]i.

Adenosine Diphosphate↗
PubMed1999

Pharmacokinetic interaction between diltiazem and tolbutamide.

The effect of co-administered tolbutamide and diltiazem on each drug's pharmacokinetics was studied in eight healthy male volunteers aged 21-25 years, with a 3 x 3 randomised crossover design. Each subject received orally 60 mg of diltiazem hydrochloride or 500 mg of tolbutamide, or both drugs. The washout period between each treatment was 7 days. Serum levels of diltiazem and tolbutamide were determined by HPLC. Serum profiles were analysed using a non-compartmental model. There was no change in the pharmacokinetics of diltiazem in the presence of tolbutamide. There was approximately 10% increase in AUC0-24 and Cmax for tolbutamide in the presence of diltiazem.

Adult↗