Activity of sulfur-containing intermediate metabolites of spironolactone

Abstract

The renal antimineralocorticoid activity of single administration of 2 sulfur-containing compounds, which are thought to be intermediate metabolites of spironolactone, was assessed in healthy subjects. They were each active in reversing the urinary electrolyte changes indiced by fludrocortisone for 2 to 10 hr after dosing, but only the 7 alpha-thiomethyl derivative exhibited activity in the period 12 to 16 hr after treatment. The activity of both drugs was less than of spironolactone. Taking urinary log 10 Na/K as the best index of antimineralocorticoid activity, the potencies of the intermediates relative to spironolactone were 0.26 (95% confidence limits, 0.12 to 0.49) for 7 alpha-thio-spirolactone and 0.33 (95% confidence limits, 0.15 to 0.62) for 7 alpha-thiomethyl-spirolactone in the period 2 to 10 hr after medication. We conclude that these minor sulfur-containing intermediate metabolites of spironolactone are unlikely to contribute significantly to the renal antimineralocorticoid activity of spironolactone.

Influence of spironolactone on neonatal screening for congenital adrenal hyperplasia

“…However, in this study an actual additive effect of spironolactone on the value of 17OHP was observed with the drug blood concentration at more than 10 ng/ml (fig 1). This indicates that if the blood concentration of spironolactone exceeds 10 ng/ml, it seems to affect the 17OHP concentration, especially in the extraction assay, where lipophilic compounds such as spironolactone and its metabolites, canrenone and sulphur containing intermediate metabolites,20 are preferentially extracted.…”

Relative potency and structure activity relationships of aldosterone antagonists in healthy man: correlation with animal experience.

“…In the three-phase studies, a further 0.5 mg fludrocortisone was taken immediately thereafter and the subjects ate a prescribed light breakfast. Urine was again collected from 09.00 h until 13.00 h. This modification of the basic procedure allows examination of the later phases of activity of the antagonists (McInnes et al, 1980;Ramsay et al, 1975a). Urine and venous blood for laboratory screening, including urinalysis, blood urea, electrolytes, liver function tests and haematology, were sampled 12 h before and after each medication and 1 week after completion of each study.…”

“…Provided the slopes were significant and there was not significant contraindication to either linearity of parallelism, the validity of the parallel line bioassay was accepted and the potency of the new aldosterone antagonists relative to spironolactone were estimated with 95% confidence limits. Data for four compounds have been published previously (McInnes et al, 1980;Ramsay et al, 1975aRamsay et al, , 1976.…”

“…Only SC28666 had no significant renal antimineralocorticoid activity. Although each drug was administered at only one dose level, it was possible to estimate their potencies relative to spironolactone using an approach previously described (McInnes et al, 1980(McInnes et al, , 1981a. The variable used in these estimations, urinary log() Na/K, is generally considered to be the best single index of mineralocorticoid (Johnson, 1954) and antimineralocorticoid activity (Gantt & Dyniewicz, 1963;Kagawa, 1964).…”

Metabolites of Antihypertensive Drugs

“…These 2 metabolites are, respectively, 0.68 and 0.33 times as potent as spironolactone (McInnes et al 1980;Ramsay et al 1977). Canrenone and 7a-thiomethyl-spironolactone are its major active metabolites, and their plasma concentrations are 3 to 5 times higher than that of the parent drug at steady-state.…”