Nonlinear pharmacokinetics of propafenone in rats and humans: application of a substrate depletion assay using hepatocytes for assessment of nonlinearity.

Linear pharmacokinetic profiles of propafenone in female Wistar rats were found after oral administration of up to 20 mg/kg. These profiles differed from nonlinear pharmacokinetics in a dose-dependent manner with increasing plasma concentrations in humans (Hollmann M, Brode E, Hotz D, Kaumeier S, and Kehrhahn OH (1983) Arzneim-Forsch 33:763-770). We investigated the species differences in pharmacokinetics of propafenone between rats and humans. In rats, after intravenous administration, clearance was constant at all doses examined (0.2-10 mg/kg), whereas the distribution volume at a steady state increased and the resultant elimination half-life was prolonged with increasing doses. In a substrate depletion assay without plasma, rat and human hepatocytes showed a concentration-dependent elimination of propafenone with low Km values (<0.4 microM). However, in the depletion assay with plasma incubation, the profiles were altered to a concentration-independent profile in rat but not human hepatocytes. The differing effect of adding plasma in rat and human hepatocytes can be explained by species differences in plasma binding (unbound fraction, 0.0071 versus 0.0754 for rats and humans, respectively, at 0.1 microg/ml). In rat plasma, the unbound fraction increased with concentrations of 0.1 to 1.0 microg/ml, whereas it was constant in human plasma. Accordingly, the in vivo nonlinear disposition in humans can be ascribed to the saturation of hepatic metabolism due to the low Km values. In contrast, the influence of saturable metabolism is canceled out with nonlinear plasma binding in rats leading to the apparent linear pharmacokinetic behavior. The newly developed depletion assay with plasma incubation gave insights into the nonlinear pharmacokinetics of propafenone.