PHARMACOKINETICS OF THE ANTIARRHYTHMIC AGENT TIRACIZINE - STEADY-STATE KINETICS IN COMPARISON WITH SINGLE-DOSE KINETICS

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, C-max,C-ss=391.8 ng mL(-1) against C-max,C-sd=132.8 ng mL(-1); M2, C-max,C-ss=143.2 ng mL(-1) against C-max,C-sd=25.8 ng mL(-1)). However, significant increases of AUC (AUC(tau)=261.9 ng h mL(-1) against AUC(0-infinity sd)=182.9 ng h mL(-1)), C-max (C-max,C-ss = 75.9 ng mL(-1) against C-max,C-sd=56.9 ng mL(-1)) and t(1/2 beta) (t(1/2 beta,ss)=4.0 h against t(1/2 beta,sd) = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the t(max) of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.