The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 2.1 vs 17.2 + 8.0, p < .001), lower average plasma concentration (Cp) (1.1 + 0.6 vs 2.5 ± 0.5 ng/ml/mg daily dosage, p < .001), and higher oral clearance (1115 ± 1238 vs 264 ± 48 ml/min, p < .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p < .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype. Circulation 75, No. 4, 785-791, 1987. THE ANTIARRHYTHMIC AGENT propafenone is a fast sodium-channel blocker with weak ,3-adrenoceptor-blocking activity and demonstrated efficacy in the treatment of a variety of ventricular and supraventricular cardiac arrhythmias. none is metabolized by an hepatic oxidative pathway that is characterized by the debrisoquine metabolic phenotype. The purposes of this study were to determine in vitro and in vivo the metabolic relationships between debrisoquine and propafenone and to assess the effect of debrisoquine metabolic phenotype, not only on pharmacokinetics, but also on clinical response, concentration-response relationships, and toxicity of propafenone. MethodsPatient selection. Patients were eligible for the study if they were between 21 and 75 years old and had more than 30 ventricular ectopic depolarizations (VEDs) per hour. Antiarrhythmic therapy was indicated for treatment of arrhythmias symptomatic with syncope, near-syncope, dizziness, fatigue, or palpitations. Patients with hemodynamically unstable sustained ventricular tachycardia or a history of sudden cardiac death were excluded, as were patients with second-or third-degree heart block, severe congestive heart failure (functional class IV of the New York Heart Association), hepatic or renal insufficiency, or terminal illness.Determination of debrisoquine phenotype. Debrisoquine phenotype was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine.12' 13 A single 10 mg oral dose of debrisoquine was given 785 Downloaded from http://ahajourn...

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Studies were performed in 13 healthy subjects to determine whether treatment with rifampicin results in induction of the metabolism of mephenytoin. Daily dosing with 600 mg rifampicin for 22 days caused a three to eightfold increase in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug to extensive metabolizers of the anticonvulsant. This was accompanied by a 40 to 180% increase in the 0-8 h urinary excretion of the 4'-hydroxy metabolite. Four weeks after discontinuing rifampicin, both metabolic indices had returned to their baseline values. By contrast, rifampicin had no effect on either measures of metabolism in subjects of the poor metabolizer phenotype. Thus, it appears that the activity of the enzyme (P-45OMp) mediating the genetically determined 4'-hydroxylation of S-mephenytoin can be significantly modulated by enzyme inducing agents such as rifampicin and possibly environmental agents with a similar ability.Keywords mephenytoin genetic polymorphism induction of metabolism rifampicin interaction

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