Nonlinear kinetics and pharmacologic response to mibefradil.

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacology

Background:

• Oral mibefradil doses (10-320 mg) decrease apparent oral clearance, while IV doses (up to 80 mg) do not affect systemic clearance.
• Understanding the mechanisms behind mibefradil's zero-order kinetics is crucial for optimizing its therapeutic use.

Purpose of the Study:

• To investigate the pharmacokinetic mechanisms responsible for zero-order kinetics observed with oral mibefradil administration.
• To evaluate the impact of repeated oral mibefradil doses on its systemic clearance and bioavailability.

Main Methods:

• Ten volunteers received 50 mg/day oral mibefradil for 8 days, with IV deuterated mibefradil on days 1 and 8.
• An additional ten volunteers received 100 mg/day oral mibefradil, following the same protocol.
• Plasma mibefradil concentrations were measured using liquid chromatography-mass spectrometry; vital signs and ECGs were recorded.

Main Results:

• Repeated 50 mg oral mibefradil resulted in zero-order kinetics due to decreased systemic clearance.
• 100 mg oral doses (single and repeated) further reduced mibefradil clearance compared to 50 mg.
• No significant changes in mibefradil bioavailability were observed with increasing doses; however, 100 mg doses affected blood pressure, heart rate, and ECG parameters.

Conclusions:

• Repeated 50 mg or 100 mg oral mibefradil doses induce zero-order kinetics by decreasing hepatic drug extraction.
• The observed zero-order kinetics did not influence the relationship between mibefradil concentration and its pharmacological response.