Metabolism of the dihydropyridine calcium channel blockers mebudipine and dibudipine by isolated rat hepatocytes

Abstract

The prototype 1,4-dihydropyridine (1,4-DHP) nifedipine, indicated for the management of hypertension and angina pectoris, has drawbacks of rapid onset of vasodilating action and a short half-life. Several newer analogues have been designed to offset these problems and these include mebudipine and dibudipine. These analogues contain t-butyl substituents that have been selected to alter the fast metabolism without altering pharmacological activity. In this study, the metabolism of mebudipine and dibudipine by isolated rat hepatocytes has been investigated. These compounds were extensively metabolized in 2 h by oxidative pathways, analogous to those known for nifedipine, and by O-glucuronidation after hydroxylation of the t-butyl substituents. The in-vitro half-lives of mebudipine (22 +/- 7.1 min) and dibudipine (40 +/- 9.8 min) were significantly longer than that of nifedipine (5.5 +/- 1.1 min), which was investigated in parallel in this study. These newer 1,4-DHPs address the problem of the short half-life of nifedipine and have potential for further development in view of their comparable potency to nifedipine.

Effect of the Two New Calcium Channel Blockers Mebudipine and Dibudipine in Comparison to Nifedipine on Vascular Flow of Isolated Rat Kidney

“…Previous findings showed that mebudipine and dibudipine had identical pharmacological effects to the prototype 1,4-DHP nifedipine, whilst possessing some advantages such as longer biological half life, longer duration of action, slower rate of absorption, fewer side effects and more vasoselectivity [9][10][11].…”

“…Mebudipine and dibudipine also showed a high potency in inhibiting the calcium evoked spikes in Helix aspersa [12]. Newer 1,4-DHPs address the problem of short half-life of nifedipine and may therefore be suitable for further development as potential therapeutic alternative to the existing 1,4-DHPs calcium channel blockers [9].…”

“…Mebudipine [tert-butyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] and dibudipine [di-tert-butyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate], are two new 1,4-DHP calcium channel blockers synthesized by Mahmoudian et al [7] with in-vitro half-lives of 22±7.1 min and 40±9.8 min respectively that were found to be significantly longer than that of nifedipine 5.5±1.1 min [9].…”

β-Enaminonitriles in heterocylic synthesis: Synthesis of new tetrahydropyridinethione, pyridopyrimidines, pyridotriazines and dihydropyridines

“…nifadipine drug. [6][7][8][9][10][11][12][13] In continuation of this work we investigated the behaviour of 3aminocrotononitrile (1) towards some electrophilic reagents such as arylidenemalononitriles and arylidinecyanothioacetamides. Thus, it has been found that 3-aminocrotononitrile (1) reacted with arylidenmalononitriles 19a-c and arylidinecyanothioacetamides 19d,e to give dihydropyridine derivatives 24a-e. Establishing structure 24 was based on its spectral data and authentic specimen prepared from the reaction of 1 with the corresponding aldehydes derivatives 25a-e.…”

Design and evaluation of oral nanoemulsion drug delivery system of mebudipine

“…Changes in chemical structure of this molecule (i.e. substitution of methyl ester in nifedipine with t-butyl ester) have reduced the conversion rate of parent 1,4-dihydropyridine to an inactive metabolite (Bohlooli et al, 2004b). Thus, longer biological half-life (T 1/2 ) and time to reach maximum effect (T max ) is observed in MB (Bohlooli et al, 2004a).…”