Clinical Pharmacokinetics of Mibefradil

Abstract

Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Mibefradil through Heme Destruction

“…Based on the known sites of oxidation associated with CYP3A4 metabolism of mibefradil (Welker et al, 1998), multiple mechanisms of inactivation like the ones described above are possible. For instance, compounds containing tertiary amines are known to inactivate P450 enzymes through N-dealkylation to the secondary amine and subsequent MI complex formation, as observed for the calcium channel blocker diltiazem (Zhao et al, 2007).…”

State-Dependent Verapamil Block of the Cloned Human Cav3.1 T-Type Ca2+ Channel

“…T-channel blockade has been implicated in the successful treatment of hypertension. Mibefradil, a selective T-channel blocker (Mehrke et al, 1994;Mishra and Hermsmeyer, 1994;Clozel et al, 1997;Martin et al, 2000), exhibited favorable antihypertensive properties with minimal negative inotropic effects before its withdrawal from the market because of lethal drug interactions involving P450 cytochrome metabolism (Welker et al, 1998).…”

Effects of T-type calcium channel blockers on cocaine-induced hyperlocomotion and thalamocortical GABAergic abnormalities in mice

“…Control groups received three similarly timed saline injections. Since mibefradil takes longer to reach a maximum effect (~2 h; Welker et al 1998) than 2-octanol (~30 min; Sinton et al 1989), the schedule for the in vivo administration of the T-type calcium channel blockers consisted in the pre-administration of mibefradil (dissolved in sterile saline) 90 min prior to the first saline/cocaine injection, while 2-octanol (mixed with Tween-80+saline and prepared just before each injection) was injected twice 30 min before the first and third cocaine injections. Control groups received the same volume of saline (for mibefradil groups) or Tween 80+ saline (for 2-octanol groups).…”