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The described pharmacokinetic analysis involved two separate studies on nine dogs randomly assigned to three groups of three dogs each. In the first study, the effect of varying the dosage of tolazamide was examined. The second study concerned the effect of varying the dosage of oxyphenbutazone on tolazamide. A 3 x 3 Latin square was used to study both effects. Each group received each treatment, with a minimum of 1 week separating each session. THe pharmacokinetics of tolazamide followed a two-compartment open model. The hybrid rate constants, alpha and beta, were not significantly different at the three dosages when measured by a three-way analysis of variance. The only significant difference at the three dosage levels of tolazamide was in the apparent volume of distribution. In the pharmacokinetic interaction associated with intravenous administration of one dose of tolazamide and three doses of oxyphenbutazone, the apparent volume of distribution and the hybrid rate constant alpha did not change significantly while the hybrid rate constant for tolazamide, beta, seemed to decrease with increasing oxyphenbutazone.
The relative bioavailability of tolazamide was determined, in healthy male volunteers, from four different tablet formulations manufactured by direct compaction or granulation processes and the results were compared with in vitro disintegration and dissolution values. Serum tolazamide levels were determined by a high-pressure liquid chromatographic method developed in this laboratory. Serum tolazamide levels from the formulation that gave rise to rapid absorption were described by one-compartment model kinetics with a mean absorption half-time of 1.0 hr and an elimination half-life of 4.6 hr. Peak serum levels occurred at 3.3 hr after drug administration. Marked differences were observed in drug bioavailability from the four tablets, and the mean cumulative relative fraction of dose absorbed was 1.0, 0.42, 0.75, and 0.91 from Formulations A, B, C, and D, respectively. The hypoglycemic effect was closely related to serum tolazamide levels. Disintegration times did not predict in vivo tolazamide bioavailability. Dissolution rates provided an approximate rank order correlation with in vivo absorption but failed to be predictive among formulations. Currently available in vitro tests do not accurately predict tolazamide in vivo bioavailability characteristics among different formulations and manufacturing processes but may be useful to ensure lot-to-lot uniformity in bioavailability for a given formulation and specific method of manufacture.
To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.
Although chlorpropamide and tolbutamide are well recognized as causes of hepatotoxicity, there are only 3 reported cases of hepatic injury caused by a third oral hypoglycemic agent, tolazamide. In 2 of these cases, the liver-function tests returned to normal when the drug was discontinued. In the third case, the patient had cholestasis from chlorpropamide before administration of tolazamide and developed chronic liver disease. We are reporting the second instance of chronic liver disease induced by tolazamide. Our patient had been taking chlorpropamide, but she had no evidence of liver disease before administration of tolazamide. Tolazamide should be considered as a drug capable of producing hepatotoxicity that on occasion may be chronic.
The metabolic fate of tolazamide, 1-(hexahydroazepin-1-yl)-3-p-tolylsulfonylurea (1), was studied in man and in the rat using tritium-labeled 1. The metabolites were isolated in crystalline form from urine for structure determination. The crystal structure and final molecular structure of one of these, 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5), were determined using single-crystal X-ray techniques. Following oral administration of tritiated tolazamide to male humans, 85% of the radioactivity was excreted in urine during a 5-day period. In addition to being excreted in urine unchanged, tolazamide was metabolized to 1-(hexahydroazepin-1-yl)-3-p-(carboxyphenyl)sulfonylurea (2), p-toluenesulfonamide (3), 1-(hexahydroazepin-1-yl)-3-p-(hydroxymethylphenyl)sulfonylurea (4), 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5) and a labile, unidentified metabolite 6 by man. The relative amounts of these materials excreted in 0-24-h urine collections from eight subjects averaged 7, 17, 26, 10, 25, and 15% for 1-6, respectively. In the female rat, 79% of an orally administered dose of tritiated tolazamide was excreted in urine during a 5-day period as 1-4. The relative amounts of these materials excreted during the 24-h period following administration of tolazamide were 10, 5, 5, and 80% for 1-4, respectively.
At clinically achievable concentrations (10(-9) to 5 X 10(-6) M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea IC50, 10(-7) M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported; in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 X 10(-6) M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5-40 ng/micrograms membrane protein) to myocardial membranes incubated with 10(-7) M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme. Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.
Tolazamide, a new oral hypoglycemic agent, was compared with tolbutamide, a related chemical compound, for stability of control of 12 patients suffering from maturity-onset diabetes mellitus. A short 12-week study was conducted which incorporated a cross-over design and the results were examined by variance analysis after dosage was individualized to the patient's requirements. Greater stability of fasting blood sugar was found on tolazamide; patients also had less glycosuria and lower fasting blood sugar on tolazamide. Tolazamide appeared to be between five and six times as potent as tolbutamide, mg. for mg.No hepatic, renal, hematologic or symptomatic toxic reactions were observed during the total of 72 person-weeks of tolazamide therapy.
The influence of sulfonylurea drugs in enhancing the effect of endogenous insulin is well documented. Furthermore, combination therapy with sulfonylurea and insulin is effective in the treatment of type II diabetes mellitus. Therefore, to assess the efficacy of this type of combination therapy in type I diabetes, we conducted a double-blind clinical trial with tolazamide and insulin in 15 subjects with type I diabetes. The diagnosis of type I diabetes was confirmed by previous episodes of diabetic ketoacidosis and undetectable C-peptide levels in serum samples from blood drawn from patients two hours after breakfast. During the study protocol, placebo or tolazamide was randomly added to insulin and the combination therapy was continued for three months. In the placebo group, levels of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) did not alter significantly at the end of the study period. However, in the tolazamide group, levels of FPG and HbA1c markedly improved after administration of tolazamide (FPG levels before therapy, 10.8 +/- 0.9 mmol/L [mean +/- SEM]; after therapy, 6.7 +/- 0.4 mmol/L; HbA1c levels before therapy, 10.9% +/- 0.6%; after therapy, 9.6% +/- 0.5%). Therefore, adjuvant therapy with tolazamide and insulin may be beneficial in achieving adequate metabolic control in type I diabetes mellitus.
To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 +/- 0.7 to 7.6 +/- 0.5 and 7.1 +/- 0.2%, respectively, P less than .01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P less than .001). Both agents comparably increased (P less than .01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P less than .05). Tolazamide (P less than .05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P less than .05) lowered postabsorptive hepatic glucose release (from 2.8 +/- 0.3 to 2.3 +/- 0.2 mg . kg-1 . min-1), but not to normal rates (1.8 +/- 0.1 mg . kg-1 . min-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Sulfonylurea agents have been well documented to be effective in type II diabetes mellitus by increasing insulin secretion as well as by enhancing cellular binding of endogenous insulin. We have examined in 20 type I diabetic subjects the efficacy of tolazamide, a common sulfonylurea agent, as adjuvant therapy in combination with an appropriate diet and insulin. This regimen decreased the insulin dose while continuing to maintain adequate metabolic control, as reflected by fasting plasma glucose (FPG) less than 150 mg/dl and HbA1 levels less than 9%, and reduced number of hypoglycemic episodes to almost nil in a group of subjects with adequate metabolic control before institution of combination therapy. In subjects in whom metabolic control was inadequate (FPG greater than 150 mg/dl and HbA1 greater than 9%) with insulin alone, the adjuvant therapy with tolazamide improved or normalized hyperglycemia and HbA1. In 13 subjects in whom adequate metabolic control was achieved with combination therapy, metabolic control worsened on withdrawal of tolazamide while continuing insulin in the same dosage and adequate metabolic control promptly returned on reinstitution of combination therapy with insulin and tolazamide. In the remaining seven subjects, metabolic control remained adequate with combination therapy during the 4-10-mo follow-up period. This study therefore demonstrates that combination therapy with sulfonylurea agent and insulin may be beneficial in management of type I diabetes. Furthermore, this regimen may be helpful in prevention of extreme plasma glucose excursions observed in brittle diabetic individuals. A larger, long-term clinical trial with this regimen in type I diabetic subjects must be undertaken to establish this preliminary finding.
Acceleration of glucose tolerance after repetitive intravenous glucose loads (Staub-Traugott effect) has not previously been tested in non-insulin-dependent diabetes (NIDDM). Six overt, untreated subjects were administered three hourly IV glucose tolerance tests (GTT). The glucose disappearance rate (K) changed very little between loads, indicating a suppressed Staub effect. However, insulin levels increased with each load. The characteristic loss of early phase insulin release after the first intravenous glucose injection was recovered with the third injection. After four months of tolazamide treatment the fasting plasma glucose fell from 180 +/- 19 to 134 +/- 13 mg/dL. Despite dramatic potentiation of glucose-stimulated insulin release and further improvement of early phase insulin release, K values again failed to progressively rise. This paradox occurred even in three additional subjects tested after two years of tolazamide treatment, suggesting that tolazamide may not ameliorate the postreceptor defects that impede the expression of the Staub effect. The applicability of the glucose facilitatory effect to the treatment of NIDDM might be limited to subjects in whom adjunctive measures have reestablished effective tissue responsiveness to endogenous insulin.
In a retrospective study we investigated the effects of altering treatment of type II diabetes mellitus from insulin to tolazamide on weight and blood pressure. In 17 patients, weight decreased from 136 +/- 6 to 131 +/- 6% of ideal body weight (P = .01). Even though weight loss occurred, mean systolic blood pressure increased from 133 +/- 3 mm Hg to 142 +/- 4 mm Hg (P = .025). There was no difference in diastolic blood pressure on the two treatments (79 +/- 3 v 78 +/- 4 mm Hg). In an additional 10 patients whose treatment was changed from tolazamide to insulin, mean systolic blood pressure decreased from 136 +/- 1 to 124 +/- 2 mm Hg (P < .01). In spite of the potential benefits of reversal of insulin resistance and weight reduction, altering therapy of type II diabetes mellitus from insulin to tolazamide may increase blood pressure, thereby increasing cardiovascular risk.
Recent data suggests that one of the major actions of sulfonylureas is to potentiate the anabolic cellular effects of insulin. This is the first study to examine the use of sulfonylureas as adjunctive therapy in newly-diagnosed type I diabetic children. A random, prospective, double blind study over 15 months, stratified by age at diagnosis, was conducted. The treatment group (n = 13) received daily oral weight-adjusted tolazamide whereas the control group (n = 11) received placebo. Monthly comparison of the HbA1 values between groups revealed no statistical difference; likewise, the fasting serum C-peptide values were not dissimilar. The mean daily insulin dose per kilogram, however, was less in the tolazamide group (P less than 0.001). The data suggests that the addition of tolazamide may not be of therapeutic benefit in newly diagnosed juvenile diabetics, although insulin requirements may be reduced.
The sulfonylurea hypoglycemic agent tolazamide is thought to be a rare cause of jaundice and to exhibit no hepatic cross-sensitivity with other sulfonylurea compounds. We have described a patient who had self-limited cholestatic jaundice after treatment with chlorpropamide. Subsequent treatment with tolazamide resulted in recurrence of jaundice, which disappeared after cessation of treatment. Tolazamide may exhibit hepatic cross-sensitivity with chlorpropamide.
Glucose and insulin secretory response patterns during glucose tolerance tests were determined in 28 maturity-onset diabetics, and the sequential effects of diet and a sulphonylurea, tolazamide, were assessed. Untreated diabetics showed hyperglycaemia, increased serum immunoreactive insulin response patterns, delayed insulin release, and relative insulin deficiency. Diet alone partially corrected the hyperglycaemia and serum immunoreactive insulin response but had no effect on the delayed insulin release or relative insulin deficiency. Tolazamide plus diet restored all values towards normal. The net effect of maintenance tolazamide therapy was to (1) restore the insulin secretory response pattern to normal, (2) reduce total pancreatic insulin output, and (3) improve the efficiency of insulin secretion. The results suggest that there is a rational basis for the use of sulphonylurea in all maturity-onset diabetics, including patients with mild carbohydrate intolerance and those who are apparently controlled by diet alone.
The effect of tolazamide on in vitro rates of gluconeogenesis, ketogenesis, and glycogenesis was determined in liver tissue from fasted normal and diabetic rats. Hormones were not added to the incubation mixture. Two concentrations of the drug were tested, one of which was therapeutic (40 micrograms/ml) and other immoderately elevated (400 micrograms/ml). Neither drug concentration affected hepatic glycogen synthesis. However, the low dose of tolazamide inhibited ketogenesis in the diabetic liver by 39% and in the control liver by 32%; oxidative CO2 production from palmitate was reduced in parallel with ketogenesis. The drug did not alter ketogenesis in isolated intact mitochondria. Similarly, this same therapeutic dose curtailed hepatic gluconeogenesis only in control liver (74% inhibition); this reaction was unaltered by this drug concentration in the explants derived from the diabetic rats. The logarithmically higher dose inhibited hepatic gluconeogenesis in both control and diabetic liver tissue by 56% and 51%, respectively. Hence, possibly acting at a postreceptor site, therapeutic concentrations of tolazamide can decrease rat hepatic in vitro gluconeogenesis and ketogenesis.
A bioassay of the hypoglycemic drug tolazamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered tolazamide at one of two doses, either 5,000 or 10,000 ppm, for 103 weeks. Matched controls consisted of 15 rats and 15 mice of each sex. All surviving rats and mice were killed at 104 or 105 weeks. Survival rates for the dosed rats of each sex were higher than those for the matched controls, and were adequate for the development of late-appearing tumors. Survival rates for the mice were lower than those for the rats, particularly for the dosed females (matched controls 67%, low-dose 34%, high-dose 32%). However, a large number of these deaths in the dosed females occurred after 90 weeks on study, and survival of both males and females was adequate for the development of late-appearing tumors. All observed tumors were of types commonly found in the strains of animals used, and there were no statistically significant increases in the incidence of tumors in the dosed animals as compared with controls. It is concluded that under the conditions of this bioassay, tolazamide was not carcinogenic for Fischer 344 rats or B6C3F1 mice.