Pharmacokinetics in man of a new antiarrhythmic drug, cibenzoline

Abstract

The kinetics of cibenzoline (UP 339.01), a new antiarrhythmic drug, was studied after i.v. and oral administration to 5 healthy subjects. Cibenzoline levels in plasma and urine cibenzoline were measured by a GLC method. After i.v. administration, the total clearance was 826 ml . min-1. The fraction of cibenzoline excreted unchanged in the urine was 0.602 and it was correlated with the creatinine clearance. After i.v. and oral administration, the renal clearances were 499 ml . min-1 and 439 ml . min-1, and the half-lives were 4 h 01 min and 3 h 24 min, respectively. The differences were not significant. Availability by the oral route was 0.92, the maximum plasma concentration being observed at 1 h 36 min. The results were compared with those for other antiarrhythmic drugs.

Effect of Cibenzoline, a Class I Antiarrhythmic Drug, on Action Potential in Canine Ventricular Muscle

“…In our laboratory cibenzoline suppressed all experimental canine ventricular arrhy thmias induced by coronary ligation, digitalis or adrenaline (14). A particularly interesting thing is that the cibenzoline concentrations used were therapeutically relevant (1-5 x 10-6 M) (15,16). Miura et al (17) found that cibenzoline provided protection against ven tricular tachycardia induction in 16 of 33 patients.…”

Quantification of Cibenzoline by Enzyme-Linked Immunosorbent Assay

“…As much as 60％ of the oral dose appeared intact in the urine. 7) Metabolic studies in humans 18) and dogs 19) indicate that cibenzoline is the predominant excretion product in urine. Three metabolites were identiˆed in human plasma or urine in quantiˆable amounts: 4,5-dehydrocibenzoline, p-hydroxycibenzoline, in both free and conjugated forms and p-hydroxybenzophenone.…”

“…1) It is a widely used antiarrhythmic drug that is useful in the treatment of both ventricular and supraventricular arrhythmias, and adverse eŠects due to this drug have been minor and infrequent; 2,3) however, there have been several reports of hypoglycemia, occasionally associated with excessive insulin secretion, in patients receiving cibenzoline, both at overdose and at therapeutic plasma concentrations. 4 6) It is eliminated primarily by renal excretion, with about 60％ of an administered dose recovered in the urine as unchanged drug; 7) therefore, in patients with reduced renal function, side eŠects such as hypoglycemia have been reported. It is necessary to adjust the administration interval and dosage according to the renal function.…”

Heart Failure Elevates Serum Levels of Cibenzoline in Arrhythmic Patients

“…The renal excretion of cibenzoline is reduced in patients with impaired renal function, 6 because approximately 60% of the cibenzoline dose is excreted in urine as the parent drug. 10,11 Renal function may be an important factor in the dosage decision for patients treated with cibenzoline. In addition, the present study demonstrated that the C/D values of cibenzoline in patients with heart failure were significantly higher than those in patients without heart failure.…”