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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.

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Relative dose ratios of the mineralocorticoid antagonists spironolactone (100 mg and 200 mg daily) and canrenoate-K (200 mg daily) at steady state were defined in six healthy subjects with fludrecortisone as the mineralocorticoid agonist. The urine log 10 Na/K responses during spironolactone treatments were consistent with the law of mass action. The potency of canrenoate-K was 0.68 (95% C.L. 0.53 to 0.89) that of spironolactone on a weight basis. Approximately 72% of the renal antimineralocorticoid activity of spironolactone could attributed to the metabolite canrenone. The results at steady state are contrasted with those of a previously study comparing single doses of spironolactone and canrenoate-K.

The bioavailability and pharmacologic activity of tablets containing micronized spironolactone chemical (median particle size 2.21 micrometers) were compared to those of tablets made from standard spironolactone chemical (median particle size 78.8 micrometers) in healthy men. Apart from particle size, all features of these tablets were identical. After 200-mg single doses, the bioavailability of micronized tablets was significantly higher than that of standard tablets. Furthermore, as assessed by 24-hour urine log10 10 Na/K ratio, the pharmacologic activity of micronized spironolactone was significantly greater than that of the standard formulation. The significant influence on renal antimineralocorticoid activity of raised plasma and urinary levels of canrenone, quantitatively the major active metabolite of spironolactone in man, emphasizes the clinical importance of the bioavailability of spironolactone preparations. Since this study, the process used in the manufacture of spironolactone (Aldactone) tablets has been under review.