A. Skerjanec et al., MECHANISMS OF NONLINEAR PHARMACOKINETICS OF MIBEFRADIL IN CHRONICALLYINSTRUMENTED DOGS, The Journal of pharmacology and experimental therapeutics, 278(2), 1996, pp. 817-825
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.