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

Bohlooli, S. and Mahmoudian, M. and Skellern, G.G. and Grant, M.H. and Tettey, J.N.A. (2004) Metabolism of the novel dihydropyridine calcium channel blockers mebudipine and dibudipine by isolated rat hepatocytes. Journal of Pharmacy and Pharmacology, 56. pp. 1469-1475. ISSN 0022-3573

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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.