Canrenone—the Principal Active Metabolite of Spironolactone?

Abstract

I The properties of the aldosterone antagonists spironolactone and potassium canrenoate in tablet formulations were examined in two studies in healthy subjects, the first study comparing levels of their common major metabolite, canrenone, in plasma and the second study comparing the pharmacological activity of the two drugs in reversing the renal effects of the synthetic mineralocorticoid fludrocortisone. 2 At equal dosage by weight potassium canrenoate yielded peak levels and areas under the curve for canrenone in plasma which were significantly lower than those for spironolactone, and the peak level of canrenone was reached significantly later. Comparison with published work suggests that the experimental formulation of potassium canrenoate had low bioavailability. 3 Spironolactone produced statistically valid log dose-response curves against fludrocortisone as regards sodium excretion, potassium retention and increased urine sodium to potassium ratio. There was no significant log dose-reponse after potassium canrenoate, and a statistically valid estimate of relative potency could not be obtained. 4 The results of the two studies seem inconsistent with the view that canrenone alone is responsible for the pharmacological activity of both drugs, and suggest that a significant part of the activity of spironolactone may be attributable to metabolites other than canrenone.

Spironolactone dose‐response relationships in healthy subjects.

“…A valid comparison of the spironolactone doseresponse relationships for sodium excretion and potassium excretion is difficult due to the paradoxical behaviour of the sodium response but they seem to be dissociated both in duration of activity and in dose producing maximal response. Furthermore, the slopes of Ramsay et al (1976b) dMcInnes et al ( 1981a) e Mclnnes et al (1981c) the dose-response curves for natriuresis were steeper than those for antikaliuresis, which is in keeping with previous experience with this model (Ramsay et al, 1975(Ramsay et al, , 1976a.…”

Activity of sulfur-containing intermediate metabolites of spironolactone

“…The antialdosterone action of spironolactone cannot readily be ascribed to the parent drug, since its elimination half-life is so short" that most workers have failed to detect it with certainty in biological fluids. 2, 7, :J2 Spironolactone undergoes extensive metabolism, and, of the unconjugated metabolites, canrenone is found in highest concentrations-t8-20 and until recently was assumed to be the major active metabolite.f" This may well be so after repeated administration;" but studies in animals-" and man'": 26 have shown that this is not the case after single doses of spironolactone, These studies led Ramsay et al 25 to suggest that sulfurcontaining metabolites may be responsible for the greater part of the activity of single doses of spironolactone. Neither of the sulfur-containing compounds tested in this study have been positively identified in blood or urine, but they are the logical precursors of the sulfur-containing metabolites isolated from human urine.…”

Spironolactone and canrenoate‐K: Relative potency at steady state

“…tone in animals l l or in man, 8,20,22 and we have shown that single doses of canrenoate-K have renal antimineralocorticoid activity significantly less than that of spironolactone in healthy man, with a relative potency (canrenoate-K:spironolactone) of 0.31: 1. 20 We carried out the present study because there was reason to believe that on repeated dosing the difference in potency between the two drugs would be reduced.…”