Steady-state pharmacokinetics of oral cibenzoline in man.

Abstract

Cibenzoline, a new antiarrhythmic drug, was studied in five healthy male volunteers to evaluate its steady-state pharmacokinetics after oral dosing. The subjects were given a single dose of 150 mg of cibenzoline succinate, followed three days later by 150 mg three times a day at 9 am, 2 pm and 7 pm on day 1 to day 7, and once at 9 am on day 8. The plasma and urinary concentrations of cibenzoline and its dehydro metabolite were determined by high performance liquid chromatography. The plasma half-life of cibenzoline after the last dose of multiple dosing (6.56 hr) was longer than that after single dosing (5.12 hr), whereas urinary half-life estimated from urinary excretion rates was actually the same for single dosing (6.40 hr) and multiple dosing (6.49 hr). The percent of the given dose recovered in the urine during multiple dosing (73.9 %) was higher than that during the first 48 hours after single dosing (48.9 %). The plasma concentrations of cibenzoline obtained each from single and multiple dosing were well fitted to a two-compartment model with zero-order absorption. The model-dependent analysis showed a 22 % decrease in total clearance by multiple doses. This is mainly due to a 54 % decrease in extra-renal clearance. The decrease in clearance was suggested to be transient, and the trough plasma concentrations and urinary excretion rates reached steady state on the second day of multiple dosing. The maximum plasma concentration of dehydro metabolite after single dosing was about 1/20 times that of cibenzoline, and was nearly the same as that after multiple dosing. The trough plasma concentrations of the metabolite reached steady state after the first dose of multiple dosing. Cibenzoline was well tolerated. Clinically significant adverse effects attributable to the drug were not observed.