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

Abstract

1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10 Na/K, the relative potency of SC8109: spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04-0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.

Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.

“…In general, the urinary electrolyte findings confirm our previous experience with the drugs (McInnes et al, 1981). The natriuretic potency of prorenoate potassium relative to spironolactone (3.6, 95% confidence limits, 1.6-10.4) was neither statistically inconsistent with the results from the dose-ratio approach (4.2, 95% confidence limits, 2.7-6.9) (McInnes et al, 1981) nor contraindicated a two-fold increase in relative potency with regard to single dose studies (Ramsay et at., 1975a, b).…”

“…The wide confidence limits of this estimate indicate its imprecision, a consequence of the shallow aldosterone antagonist dose-response trends. It seems unlikely that this resulted from excessive mineralocorticoid challenge in view of the results for urinary sodium excretion and the similar potassium responses with lower doses of fludrocortisone in previous studies (McInnes et al, 1981;Ramsay et al, 1977a). At steady state, dose-responses for potassium excretion may indeed be shallow or confounding homeostatic influences may conceal the true relationship.…”

“…As in studies using the dose ratio approach (McInnes et al, 1981;Ramsay et al, 1977a), an acceptable estimate of relative potency for potassium excretion was precluded although a statistically valid estimate was possible for urinary potassium concen- (Ramsay et al, . 1977b.…”

“…The drugs were compared with respect to their renal antimineralocorticoid activity and, in view of the information from previous studies (McInnes et al, 1981;Ramsay et al, 1975a) and the clinical role of aldosterone antagonists, potassium sparing properties were studied in detail. Plasma concentrations of prorenone, the only known active metabolite of prorenoate potassium (Claire et al, 1979;Funder et al, 1974Funder et al, , 1976 and canrenone, quantitatively the major active metabolite of spironolactone in men (Karim et al, 1976a) (Figure 1), were measured comprehensively to establish that steady state conditions had been reached and to ensure that there were no important qualitative differences in the respective plasma concentration-time curves.…”

Spironolactone dose‐response relationships in healthy subjects.

“…Likewise, relating the findings from single dose studies to the clinical situation where the drug is prescribed continuously and maximal activity is observed only after some days medication, should be cautious. However, repeated dosing studies in healthy subjects have confirmed dissociation of urinary sodium and potassium handling (McInnes et al, 1981a;Ramsay et al, 1977). The relatively narrow dose range over which the steep portion of the potassium excretion relationship is encountered may explain the difficulties in discriminating between the urinary potassium responses to different doses of spironolactone in those studies.…”