Pharmacokinetics and metabolism of bepridil

Abstract

Bepridil hydrochloride differs from the other calcium antagonists in structure as well as in several clinical pharmacokinetic characteristics. The drug is completely absorbed from the gastrointestinal tract, but first-pass extraction reduces oral bioavailability to approximately 60%. After single-dose administration, the elimination half-life of bepridil averages 33 +/- 15 hours. However, upon multiple dosing, a half-life of 42 +/- 12 hours is found. As with verapamil and diltiazem, bepridil clearance is decreased after multiple dosing. Bepridil is completely metabolized, presumably by hepatic oxidative processes. A total of 17 metabolites have been identified, but the contribution of any of these metabolites to observed clinical response is currently unclear. The free fraction of bepridil in plasma is low, averaging only 0.23%. Despite this high protein binding, in vitro studies indicate that the potential for drug-to-drug interactions based on displacement of bepridil from its binding sites is low. Bepridil follows a linear dose/plasma concentration relation after single and multiple doses of the drug in both healthy volunteers and patients with angina. However, mean steady-state plasma bepridil concentrations are higher in patients, indicating a greater average decreased clearance. Food does not interfere with bepridil absorption. At this time, no significant pharmacokinetic interactions between bepridil and digoxin have been detected.