Food Enhances Bioavailability of the New Antiarrhythmic Agent Tiracizine by Affecting its Hepatic First-Pass Metabolism: Evidence by Serum and Urine Metabolite Kinetics.
The serum and urine kinetics of tiracizine, a new class I antiarrhythmic agent, and three of its metabolites were assessed in eight healthy extensive metabolizers after a single oral administration of 100 mg tiracizine in fasted state and after a standard breakfast. Additionally, ECG changes caused by tiracizine were compared between the two states. With food, the mean A(0minus signinfty infinity) value of the parent compound was significantly increased (560.7 versus 419.0 ng h ml(minus sign1)). The amount excreted unchanged in urine (percentage of the dose) rose significantly (2.43% versus 1.78%). However, mean AUC(0--32 h) and C(max) as well as urinary excretion of the 3-amino-5-methylamino-acetyliminodibenzyl metabolite were decreased (1152.8 versus 1328.0 ng h ml(minus sign1), 43.6 versus 56.1 ng ml(minus sign1), and 8.59 versus 11.95%, respectively). Total urine recovery (sum of individual tiracizine and metabolite excretion) tended to decrease (31.1% versus 36.1%). Serum and urine metabolite kinetics indicate that food-induced enhancement of tiracizine bioavailability is caused by an alteration in hepatic first-pass metabolism. Reduced N-demethylation is considered to be the limiting step. Tiracizine-induced PQ and QRS prolongations in the ECG tended to be more pronounced with food. Due to the serum concentration dependence of these ECG alterations, food intake might alter the antiarrhythmic efficacy of tiracizine at higher doses. Therefore, patients should be advised to take tiracizine in a constant relationship to food to assure consistent bioavailability.
Berndt
Annette
A
Oertel
R.
R
Richter
K.
K
Gramatté
Th.
T