Relative potency of prorenoate and spironolactone in normal man

Abstract

The potency of single doses of a new aldosterone antagonist, prorenoate, in reversing the renal effects of the synthetic mineralocorticoid fludrocortisone was compared to that of spironolactone in a double-blind balanced crossover study in 12 healthy subjects. The potency of prorenoate potassium as related to elevation of the urinary log 10 10 Na/K ratio (2.69:1) and as related to potassium retention (3.75:1) was significantly higher than that of spironolactone. Prorenoate produced greater natriuresis (1.64:1) but the difference was not significant. There was evidence for a qualitative difference between spironolactone and prorenoate; the latter significantly more potent in retaining potassium than in increasing sodium excretion. The simple methodology described is based on standard bioassay principles, yielded a valid and sensitive comparison of the two drugs, and should prove useful in the evaluation of other aldosterone antagonists.

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

“…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) …”

Plasma uric acid and spironolactone response in healthy subjects.

“…Statistical methods used were the analysis of variance and product moment correlations. Log transformation of the urine Na/K ratio was used as this provides a sensitive index of response to mineralocorticoid antagonists (Ramsay, Harrison, Shelton & Tidd, 1975). …”

Relative potency of prorenoate potassium and spironolactone in attenuating diuretic induced hypokalaemia.

“…Prorenoate potassium ( Figure 1) also possesses properties compatible with competitive antagonism of both endogenous and exogenous mineralocorticoids (Hofmann et al, 1975;Levine et al, 1976;Ramsay et al, 1975. On a weight basis, this drug is more potent than spironolactone in altering urine electrolyte excretion following fludrocortisone challenge in man (Levine et al, 1976; McInnes etal., 1981, 1982cRamsay etal., 1975Ramsay etal., , 1976) but repeated dose comparisons using this method have been unable to provide a satisfactory estimate of its potency relative to spironolactone as a potassium sparing agent (McInnes et al, 1981(McInnes et al, , 1982c with diuretics alone or in combination with spironolactone and thereafter there is little recovery despite continued treatment (Leemhuis & Struyvenberg, 1973;McInnes et al, 1982b;Maronde et al, 1969).…”