[Significance of the degree of oxidative hepatic metabolism in conditioning the pharmacokinetics and the pharmacodynamics of propafenone]

Abstract

The aim of this study was to evaluate plasma concentrations of propafenone (P) and 5-hydroxy-propafenone (5-OH-P) at steady state in 36 patients with ventricular premature beats, Lown class greater than or equal to 2, submitted to antiarrhythmic treatment with propafenone either in acute administration (AA) (300-450 mg) or in chronic administration (CA) (150-300 mg t.i.d. for 14-21 days followed by a wash out), and to define the relationship existing between metabolic oxidative capacity and P and 5-OH-P pharmacokinetics and pharmacodynamics. Antiarrhythmic treatment resulted efficacious in 31/36 cases (86%) during AA and in 28/36 cases (78%) during CA. At steady state a wide interindividual variability was observed in plasma concentrations of P (mean = 835 +/- 619 ng/ml, coefficient of variation = 74%), in plasma concentrations of 5-OH-P (mean = 142 +/- 93 ng/ml, coefficient of variation = 65%) and of their ratio (mean = 6.51 +/- 8.53, coefficient of variation = 131%), without significant differences between responders and nonresponders. In a subgroup of 14 subjects, characterized as extensive oxidizers of dbrisoquine, a significant correlation (r = 0.97, p less than 0.001) was observed between the ratio of P and 5-OH-P plasma concentrations at steady state and oxidative metabolic capacity (expressed as debrisoquine/4-hydroxy-debrisoquine ratio). Oxidative metabolic capacity was also correlated with P half life (r = 0.82, p less than 0.002 in AA and in CA) and with the ratio of P and 5-OH-P area under curve (r = 0.91, p less than 0.001 in AA and r = 0.90) changes at the electrocardiogram (mean values = + 20% for QRS, +26% for PR). In conclusion, oxidative metabolic pathway is a crucial point in propafenone metabolization; indeed the extent of metabolic oxidative capacity, evaluable by analysis of debrisoquine oxidation, is responsible for a wide interindividual variability of P and 5-OH-P plasma concentrations, present even in a population of debrisoquine extensive oxidizers and, moreover, influences the extent of electrocardiographic changes of PR and QRS intervals, which are related to 5-OH-P plasma levels, but not to P plasma levels.