@article {Skerjanec817, author = {A Skerjanec and S Tawfik and Y K Tam}, title = {Mechanisms of nonlinear pharmacokinetics of mibefradil in chronically instrumented dogs.}, volume = {278}, number = {2}, pages = {817--825}, year = {1996}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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) received 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 showed that hepatic clearance and systemic clearance values were similar (20.1 +/- 5.5 vs. 18.5 +/- 4.4 ml/min/kg, P \> .05), suggesting that the liver is the main eliminating organ. The fraction of the administered dose absorbed from the gut after all p.o. treatments was approximately 60\%, indicating that incomplete absorption and/or first-pass gut metabolism occurred. The fraction absorbed was not altered by dose or duration of treatment. The absolute bioavailability, however, was increased 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 are the result of an increase in bioavailability and a reduction in systemic clearance. Both changes are attributed to a reduction in the ability of the liver to eliminate the drug.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/278/2/817}, eprint = {https://jpet.aspetjournals.org/content/278/2/817.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }