Pharmacodynamics of Cibenzoline-Induced Hypoglycemia in Rats

Abstract

Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

“…Furthermore, the estimated glucose half-life (approximately 10.2 min) calculated by the k in,Glu /C Glu(0) value in the present study was similar to previously reported values (approximately 15.6-43.8 min). [33][34][35] Thus, under conditions in which the glucose-induced secretion of insulin and effects of insulin on glucose utilization are not impaired, a simple model such as ours appears to be sufficient to describe the kinetics of glucose.…”

Combined sepsis‐ and renal dysfunction‐induced hypoglycaemia in an older patient taking cibenzoline

“…This provides a potential mechanism for cibenzoline-induced hypoglycaemia. 21,22 Unfortunately, we did not implement insulin measurement in this case, but these proposed mechanisms may explain the occurrence of hypoglycaemia in our patient, despite maintaining cibenzoline blood concentrations within the therapeutic range.…”

Hypoglycemic Coma Induced by the Use of Succinic Acid Cibenzoline in Frail Late-stage Elderly Subjects

“…In addition, it is known that this medicine functions as an ATP-sensitive potassium (KATP) channel blocker and thereby facilitates endogenous insulin secretion from pancreatic β-cells, which can lead to the onset of hypoglycemia (4,5). We herein report two frail, late-stage elderly subjects who experienced a severe and prolonged hypoglycemic coma after the administration of CZ.…”