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 an tiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administr ation of 50 mg tiracizine and during steady state (50 mg b.i.d.). Addi tionally, tiracizine-induced ECG changes were measured. Considerable a ccumulation of M1 and M2 was observed during repeated dosing (M1, C-ma x,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, signi ficant increases of AUC (AUC(tau)=261.9 ng h mL(-1) against AUC(0-infi nity sd)=182.9 ng h mL(-1)), C-max (C-max,C-ss = 75.9 ng mL(-1) agains t C-max,C-sd=56.9 ng mL(-1)) and t(1/2 beta) (t(1/2 beta,ss)=4.0 h aga inst t(1/2 beta,sd) = 2.4 h) of the parent compound indicate non-linea r kinetics. The significant decrease in renal clearance of all four su bstances as well as the decrease of non-renal tiracizine clearance wit h repeated dosing led to the assumption that non-linearity is due to s aturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminate d 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 tiraciz ine.