Spironolactone and potassium canrenoate in normal man

Abstract

The pharmacological activity of single doses of the two aldosterone antagonists, potassium canrenoate and spironolactone, was examined in two studies in healthy volunteers. Both drugs were active in reversing urinary electrolyte changes induced by fludrocortisone in periods 2 to 16 hr after treatment. Potassium canrenoate was significantly less potent that spironolactone on a weight or molar basis, with best estimates of the relative potency potassium canrenoate: spironolactone of approximately 0.3:1. On a weight basis the two drugs yielded plasma levels of the metabolite canrenone which were approximately equivalent. The results indicate that canrenone is not the principal pharmacologically active metabolite of spironolactone. Our study suggests that a major part of the renal antimineralocorticoid activity of spironolactone may be attributable to minor sulfur-containing metabolites or their precursors having a high renal clearance that affords access to their site of activity via the renal tubular fluid.

Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.

“…Doubts have been expressed concerning the analogy of this model which employs single doses of aldosterone antagonists in healthy human subjects pre-treated with the synthetic mineralocortisoid, fludrocortisone, with the clinical situation where the maximum effects of the drugs may not be seen for several days of continuous administration and where endogenous aldosterone is the agonist (Ramsay, Harrison etal., 1975;Ramsay, Hessian & Tidd, 1975;Ramsay et al, 1976). However, the good agreement of our results with clinical evidence suggests that acute human volunteer studies employing this method may have predictive value.…”

“…In this study, the single dose oral potency of SC8109 relative to spironolactone was estimated in healthy human volunteers using a parallel line bioassay which has been employed previously to estimate the relative potency of competitive mineralocorticoid antagonists (McInnes, Shelton et al, 1980;Ramsay, Harrison et al, 1975;Ramsay et al, 1976). Although not compared to placebo, the significance of the log SC8109 dose-response relationship for urinary loglo 10 Na/K, considered the best single index of renal mineralocorticoid (Johnson, 1954) and antimineralocorticoid activity (Gantt & Dyniewicz, 1963;Kagawa, 1964), and the lack of contraindication to its linearity and parallelism with the log spironolactone dose-response trend for the same variable indicate that SC8109 has activity as a competitive mineralocorticoid antagonist in this model.…”

“…The method closely followed that developed by Ramsay, Harrison et al (1975) and Ramsay et al (1976) from the original observations of Ross (1962) who showed that single oral doses of the synthetic mineralocorticoid, fludrocortisone, consistently depress the sodium:potassium (Na/K) ratio in overnight urine with a log dose-response which exhibits parallelism with aldosterone. Estim-Ates of the potency of SC8109 relative to spironolactone for each log transformed parameter with respective 95% confidence limits are shown in Table 2.…”

“…Methodology, based on standard bioassay principles, allowing accurate quantitative comparison of aldosterone antagonists in healthy humans has been described (Ramsay, Harrison et al, 1975;Ramsay et al, 1976). However, while numerous structures with properties compatible with competitive mineralocorticoid antagonism have been synthesised, few have reached the clinic, and there is little comparative information in disease states.…”

“…Clinical evidence suggested a potency ratio of 2.5:1 in favour of spironolactone in its original formulation (Drill, 1962) or 10:1 for the current preparation of spironolactone (Aldactone () which has improved bioavailability (Shaldon, Ryder & Garsenstein, 1963). In this study we used the bioassay developed by Ramsay, Harrison et al (1975) and Ramsay et al (1976) …”