Abstract

Epleronone (EP) is a highly selective aldosterone receptor antagonist that has been found to reduce blood pressure when used alone or in combination with other drugs. It is well absorbed orally with a half-life ranging from 2.2 to 9.4 h. In contrast to treatment of hypertension with non-selective antagonist sprirolactone, that with EP is associated with much lower incidence of gynecomastia, mastodynia, abnormal vaginal bleeding and sexual impotence. The reduced side effects of EP is believed to be due to the presence of 1 9,11-epoxide group in the molecule. The primary route of metabolism of EP in humans is 6b-hydroxylation to produce 6b-OH-EP catalysed by CYP3A4. HEP, the open lactone ring form of EP, can also be hydroxylated to produce 6b-OH-HEP. There is no evidence for any alteration of the 9,11-eopxide ring or the methyl ester. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that neither EP nor any of its metabolites is highly labile or extremely inert. The molecular surface of EP appears to abound most in electron-deficient regions so that it can readily with cellular nucleophiles such as reduced form of glutathione and nucleobases in DNA. The depletion of cellular glutathione level is expected to induce cellular toxicity due to oxidative stress and oxidation of nucleobases in DNA will cause DNA damage.  

Key words: Eplerenone, spirolactone, aldosterone, blood pressure, CYP3A4, molecular modelling