Nonlinear pharmacokinetics of mibefradil in the dog

The pharmacokinetics of mibefradil in the dog was evaluated in this study. Single intravenous (1 mg/kg) and three oral doses (1, 3, 6 mg/kg) of mibefradil were administered to three dogs according to a randomized complete block design, where dogs were blocks and treatments randomly assigned to each block. Systemic plasma clearance, volume of distribution at steady-state and half-life after intravenous administration were as follows: ClS = 18.4 +/- 1.2 mL/min/kg, VSS = 9.7 +/- 3.8 L/kg, and T1/2 = 9.5 +/- 3.4 h. Oral plasma clearance decreased with an increase in dose, from 101.8 +/- 18.8 mL/min/kg at 1 mg/kg to 21.7 +/- 4.3 mL/min/kg at a 6 mg/kg dose (p < 0.05). Half-life values did not change significantly with an increase in oral dose in all the animals studied (10.6 +/- 1.5 h at 1 mg/kg to vs 13.4 +/- 3.5 h at 6 mg/kg). Dose-normalized AUC ratios between the oral and intravenous treatments increased from 0.18 +/- 0.03 at 1 mg/kg to 0.87 +/- 0.21 at a 6 mg/kg dose (p < 0.05). The nonlinear kinetic behavior of mibefradil is consistent with an increase in gut absorption and/or reduction in elimination after higher oral doses. Although both dogs and humans exhibit nonlinear pharmacokinetics after oral administration, there are substantial differences in the clearance and volume of distribution values between these two species. Even though these differences can, in part, be accounted for by the difference in plasma protein binding, the use of the dog as an animal model for human mibefradil pharmacokinetics need to be qualified.