MECHANISMS OF NONLINEAR PHARMACOKINETICS OF MIBEFRADIL IN CHRONICALLYINSTRUMENTED DOGS

The mechanisms of nonlinear pharmacokinetics after single-and multiple -dose treatments with a new calcium channel blocker, mibefradil, were studied. Four female, chronically instrumented dogs (22 +/- 2.1 kg) re ceived a single i.v, dose (1 mg/kg), three single p.o, doses (1, 3 and 6 mg/kg) and a regimen of 3 mg/kg p.o. doses twice per day for 8 days ; the order of treatment was randomized. Data on i.v. administration s howed that hepatic clearance and systemic clearance values were simila r (20.1 +/- 5.5 vs. 18.5 +/- 4.4 ml/min/kg, P >.05), suggesting that t he liver is the main eliminating organ. The fraction of the administer ed dose absorbed from the gut after all p.o. treatments was approximat ely 60%, indicating that incomplete absorption and/or first-pass gut m etabolism occurred. The fraction absorbed was not altered by dose or d uration of treatment. The absolute bioavailability, however, was incre ased because of a dose- and duration of treatment-dependent reduction in hepatic elimination (absolute bioavailability changing from 0.25 +/ - 0.18 at 1 mg/kg to 0.40 +/- 0.22 at 6 mg/kg and 0.48 +/- 0.14 after multiple dosing, P <.05). This change was mainly caused by a decrease of systemic clearance values from 15.6 +/- 9.7 to 9.0 +/- 1.3 and 7.0 +/- 3.5 ml/min/kg, respectively (P <.05). These data clearly indicate that the nonlinear pharmacokinetics of mibefradil after p.o. dosing ar e the result of an increase in bioavailability and a reduction in syst emic clearance. Both changes are attributed to a reduction in the abil ity of the liver to eliminate the drug.