β-Blocking Properties of Propafenone in Extensive Oxidisers: A Study on Heart Rate Behaviour during Holter Monitoring

The aims of this study were to evaluate whether the beta-blocking effect during propafenone treatment is clinically significant even in extensive metabolisers of debrisoquine (> 90% of Caucasians), and to identify the kinetic determinants of such an effect. 11 patients, classified as extensive oxidisers of debrisoquine, with stable ventricular contractions (> 100/hour) were studied by Holter monitoring in basal condition and after 14 days of treatment with propafenone 300mg 3 times daily. A complete pharmacokinetic assessment, with serial plasma samples for propafenone and 5-hydroxy propafenone determination, was performed during washout. A mean reduction in either maximum heart rate (HR max) [-7.1%] or mean heart rate (HR mean) [-4.2%] was observed during treatment with propafenone, but its extent varied within the patient population from 0 to 17%. The degree of HR slowing was related to the area under the concentration-time curve of propafenone (r = 0.725, p < 0.02 for HR max; r = 0.715, p < 0.02 for HR mean) as well as to propafenone minimum concentrations at steady-state (r = 0.809, p < 0.005 for HR max; r = 0.752, p < 0.01 for HR mean) without significant relationships to 5-hydroxy propafenone levels or to age. HR max percentage reduction during therapy was significant compared with basal values only during daytime hours (-8.1%, p < 0.005), suggesting a beta-blocking effect, and was again related to the area under the concentration-time curve of propafenone (r = 0.704, p < 0.02) and to propafenone minimum steady-state concentrations (r = 0.786, p < 0.005). A strict relationship between oxidative metabolism, evaluated by debrisoquine hydroxylation and propafenone metabolism, was observed (r = 0.982, p < 0.001). In conclusion, a beta-blocking effect during treatment with propafenone 300mg 3 times daily can be detected even by Holter monitoring performed during daily activity. However, the extent of such an effect varies widely between individuals, depending on propafenone plasma levels. The degree of oxidative metabolism is thus a major determinant of the clinical beta-blocking effect of propafenone.