Enzyme induction in the elderly: Effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone

Objective: A clinical study on enzyme induction in elderly subjects mas per formed by investigation of the effect of rifampin (INN, rifampicin) on prop afenone disposition. Propafenone was chosen as a model drug because of its complex metabolism that permits the simultaneous in vivo assessment of indu ction of phase 1 and phase 2 pathways. Methods: Six extensive metabolizers of CYP2D6 (age, 70.5 +/- 3.5 years) ing ested 600 mg rifampin once daily for 9 consecutive days. One day before the first rifampin dose and on the day of the last rifampin dose, each elderly individual received a single intravenous infusion of 70 mg unlabeled propa fenone and received a single oral dose of 300 mg deuterated propafenone 2 h ours later, Pharmacokinetics and pharmacodynamics of propafenone were compa red before and during induction. Results: Maximum QRS prolongation after oral propafenone was decreased sign ificantly by rifampin (18% +/- 5% versus 6% +/- 3%; P <.01). There were no substantial differences in pharmacokinetics and pharmacodynamics of intrave nous propafenone during induction, However, bioavailability of propafenone dropped from 30% +/- 24% to 4% +/- 3% (P <.05). After oral propafenone was administered, clearances through N-dealkylation (6 +/- 3 mL/min versus 26 /- 16 mL/min; P <.05) and glucuronidation (178 +/- 75 mL/min versus 739 +/- 533 mL/min; P <.05), but not 5-hydroxylation, were increased by rifampin, indicating substantial enzyme induction, Conclusions: Both phase 1 and phase 2 pathways of propafenone metabolism we re induced by rifampin in elderly subjects, resulting in a clinically relev ant drug interaction.