Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.
OBJECTIVE A clinical study on enzyme induction in elderly subjects was performed by investigation of the effect of rifampin (INN, rifampicin) on propafenone disposition. Propafenone was chosen as a model drug because of its complex metabolism that permits the simultaneous in vivo assessment of induction of phase 1 and phase 2 pathways. METHODS Six extensive metabolizers of CYP2D6 (age, 70.5 +/- 3.5 years) ingested 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 propafenone and received a single oral dose of 300 mg deuterated propafenone 2 hours later. Pharmacokinetics and pharmacodynamics of propafenone were compared before and during induction. RESULTS Maximum QRS prolongation after oral propafenone was decreased significantly by rifampin (18% +/- 5% versus 6% +/- 3%; P < .01). There were no substantial differences in pharmacokinetics and pharmacodynamics of intravenous 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 were induced by rifampin in elderly subjects, resulting in a clinically relevant drug interaction.