Effect of Tolazamide on Basal Ketogenesis, Glycogenesis, and Gluconeogenesis in Liver Obtained from Normal and Diabetic Rats*

Abstract

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.

Isoenergetic Polymorphism: The Puzzle of Tolazamide as a Case Study

“…For example, salts or complexesc an be formed,o rthe molecule itself can be modified. [3] In the case of sulfonylureas, conversion into salts or complexes is not the main trend for increasing their bioavailabilities, althoughm olecular complexeso fs ulfonylureas with cyclodextrin [4][5][6][7] and their salts with alkali metal ions [8,9] have been obtained.C hemical modification of the drugm olecule itself is the most widely used strategy.T he molecular structures of all the sulfonylureas are similar in their functionality at the central part of the molecule, consisting of as ulfonyl group and au rea fragment (Figure 1). It is possible to modifyt he side chains while preserving the centralf unctional groups responsible for the hypoglycemic activity.C ommon modifications are made on the benzene ring, wherein the structure and size of the R 1 group can be varied.A lternatively,t he R 2 fragment connected to the second nitrogen can be substituted with ar ange of aliphatic groups (see the Supporting Information, Figure S1).…”

“…For example, salts or complexes can be formed, or the molecule itself can be modified 3. In the case of sulfonylureas, conversion into salts or complexes is not the main trend for increasing their bioavailabilities, although molecular complexes of sulfonylureas with cyclodextrin4–7 and their salts with alkali metal ions8, 9 have been obtained. Chemical modification of the drug molecule itself is the most widely used strategy.…”

Ketone Body Metabolism in NIDDM: Effect of Sulfonylurea Treatment

“…As shown in Table 4, in NIDDM, long-term treatment with glibenclamide did not correct the interconversion between AcAc and 3-BOH and vice versa. Sulfonylureas are known to inhibit ketogenesis in vitro even in the absence of insulin (23), and Cook showed elegantly that glibenclamide is a potent inhibitor of CPT (5). However, this therapeutic effect has never been tested in vivo in NIDDM patients.…”