Propafenone undergoes extensive metabolism both by phase I and phase II enzymes: cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main metabolite 5-OH-propafenone, CYP3A4/1A2 dependent N-dealkylation and further glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an important drug interaction between rifampicin and propafenone is not to be expected a priori. However, non-CYP2D6-dependent pathways may be induced as a case report described dramatically lowered plasma concentrations of propafenone with loss of dysrhythmia control associated with rifampicin treatment. Therefore, this study aimed to investigate induction properties of rifampicin on propafenone disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once daily for nine consecutive days. The day before the first rifampicin dose and on the day of the last rifampicin dose each individual received a single intravenous (i.v.) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of 300 mg deuterated propafenone orally (p.o.). During enzyme induction maximum QRS prolongation decreased significantly after propafenone p.o. (21 +/- 7% versus 13 +/- 6% in extensive metabolizers, P < 0.01; 15 +/- 6% versus 9 +/- 6% in poor metabolizers, P < 0.01) and not after propafenone i.v. In parallel, there were no substantial differences in pharmacokinetics of propafenone i.v. by rifampicin. However, bioavailability of propafenone dropped from 30 +/- 15% to 10 +/- 8% in extensive metabolizers (P < 0.01) and from 81 +/- 6% to 48 +/- 8% in poor metabolizers (P < 0.001). Following propafenone p.o. clearances through N-dealkylation (4.1 +/- 2.1 ml/min versus 23.5 +/- 12.6 ml/min in extensive metabolizers, P < 0.01; 3.4 +/- 1.3 ml/min versus 16.0 +/- 5.5 ml/min in poor metabolizers, P < 0.001) and glucuronidation (123 +/- 48 ml/min versus 457 +/- 267 ml/min in extensive metabolizers, P < 0.05; 43 +/- 9 ml/min versus 112 +/- 34 ml/min in poor metabolizers, P < 0.01), but not 5-hydroxylation increased regardless of phenotype indicating substantial enzyme induction. Clearances to propafenone sulfate and conjugates of 5-OH-propafenone were significantly enhanced by rifampicin treatment in poor metabolizers (P < 0.01). Thus, induction of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation, sulfation) of propafenone by rifampicin resulted in a clinically relevant metabolic drug interaction which was more pronounced in extensive metabolizers than in poor metabolizers with regard to percentage decrease in bioavailability of propafenone.