The Metabolism and Biopharmaceutics of Spironolactone in Man

Abstract

Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia

“…SL has poor aqueous solubility, which is about 2.8 mg/100 mL at 25°C. 28 A high amount of surfactant and Transcutol ® probably increased the solubility of SL in the aqueous phase; thus, the drug may suffer partition from the NLCs to the aqueous medium, causing a decrease in EE%.…”

PROGRESS IN PRIMARY ALDOSTERONISM: Mineralocorticoid antagonist treatment for aldosterone-producing adenoma

“…Spironolactone is rapidly metabolized in the liver into a number of metabolites including 7a-methyl-spironolactone and canrenone. Unchanged spironolactone, 7a-methyl-spironolactone, and canrenone all have anti-mineralocorticoid activities and their mean half-lives in normal subjects are 1.4, 13.8, and 16.5 h respectively (3,4). The onset of action of spironolactone is delayed with the peak response occurring several days after the first dose, possibly because, during continuous treatment, active metabolites reach steady-state plasma concentrations only slowly (4).…”

Drugs Targeting RAAS in the Treatment of Hypertension and Other Cardiovascular Diseases

“…Both spironolactone and 7 alphathiomethylspirolactone possess anti-mineralocorticoid activity. Concomitant food intake enhances the bioavailability of spironolactone by increasing its absorption and decreasing the fi rst-pass effect [ 211 ]. The Randomized Aldactone Evaluation Study (RALES), the fi rst major clinical trial of an ARA, reported that blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduced the risk of morbidity and mortality among severe heart failure patients [ 212 ].…”