Le Ramsay

Spironolactone and potassium canrenoate in normal man.

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 than 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 anti mineralocorticoid 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.

Spironolactone and canrenoate‐K: Relative potency at steady state

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 fiudrocortisone 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 be attributed to the metabolite canrenone. The results at steady state are contrasted with those of a previous study comparing single doses of spironolactone and canrenoate‐K.

Relative potency of prorenoate and spironolactone in normal man

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.

Effect of Micronization on the Bioavailability and Pharmacologic Activity of Spironolactone

Abstract: The bioavailability and pharmacologic activity of tablets containing micronized spironolactone chemical (median particle size 2.21 μm) were compared to those of tablets made from standard spironolactone chemical (median particle size 78.8 μm) 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.

ENDOCRINE EFFECTS OF SPIRONOLACTONE IN MAN

A double blind, controlled study was carried out in order to investigate the effects of administering spironolactone, 200 mg daily, to five healthy male volunteers. The patterns of change in plasma testosterone (T) and luteinizing hormone (LH) after spironolactone were significantly different from placebo and there were significant increases in the urinary excretion of androsterone (A), aetiocholanolone (EC) and total oestrogen. Urinary dehydroepiandrosterone (DHA) excretion, after an initial rise, declined progressively during the treatment period relative to controls. The results are discussed in the light of previous observations. It is concluded that treatment with spironolactone for 2–4 days will lead to a transient rise in plasma T and urinary DHA. Continued treatment (4–10 days) is thought to cause increased LH secretion, with normalization of plasma T and DHA excretion. These changes are accompanied by increased androgen catabolism and a slightly increased conversion of androgens to oestrogens. Healthy men may therefore show alterations in sex steroid metabolism if treated for several days with high doses of spironolactone.

Furosemide and bumetanide: a study of responses in normal English and German subjects.

Diuretic responses to oral administration of 1 mg bumetanide and 40 mg furosemide were determined in double‐blind, crossover balanced trials in 10 normal English subjects and 6 normal German subjects. In each experiment the 0‐ 10 8‐hr urine volume and sodium excretion were significantly higher after bumetanide, potassium excretion did not differ, and the Na/K ratio, although higher after bumetanide, was not significantly different by analysis of variance. in German subjects the diuretic and natriuretic responses to both drugs were greater and the potassium excretion less than in English subjects. In the English, the pretreatment 24‐hr urinary NalK ratio correlated with the urinary Na/K ratio response to both drugs and with the potassium excretion after furosemide. The mean plasma uric acid before treatment correlated with the Na/K ratio and potassium excretion after furosemide. Aldosterone excretion did not correlate with response to either diuretic. The mean pretreatment 24‐hr log10 Na/K ratio in the two treatment periods of the English and German subjects correlated with the mean sodium excretion, potassium excretion, and log10 Na/K after the two diuretics, thus providing a partial explanation for intersubject and interstudy variation. Pretreatment log10 Na/K could also explain intrasubject variation, justifying its use as a covariate in covariance analysis. This demonstrated that at this dose ratio the urinary log10 Na/K ratio response to bumetanide was significantly higher than that to furosemide.

Activity of sulfur‐containing intermediate metabolites of spironolactone

The renal antimineralocorticoid activity of single administrations of 2 sulfur‐containing compounds, which are thought to be intermediate metabolites of spironolactone, was assessed in healthy subjects. They were each active in reversing the urinary electrolyte changes induced by fludrocortisone for 2 to 10 hr after dosing, but only the 7 α‐thiomethyl derivative exhibited activity in the period 12 to 16 hr after treatment. The activity of both drugs was less than that of spironolactone. Taking urinary log 10 Na/K as the best index of antimineralocorticoid activity, the potencies of the intermediates relative to spironolactone were 0.26 (95% confidence limits, 0.12 to 0.49) for 7 α‐thio‐spirolactone and 0.33 (95% confidence limits, 0.15 to 0.62) for 7 α‐thiomethyl‐spirolactone in the period 2 to 10 hr after medication. We conclude that these minor sulfur‐containing intermediate metabolites of spironolactone are unlikely to contribute significantly to the renal antimineralocorticoid activity of spironolactone.

Influence of acetylsalicylic acid on the renal handling of a spironolactone metabolite in healthy subjects

SummaryThe influence of 600 mg acetylsalicylic acid (ASA) on the renal excretion and clearance of canrenone, the principal unconjugated metabolite of spironolactone, was examined in a double-blind crossover study in six healthy subjects. ASA significantly reduced the urinary excretion, and the fractional excretion, of canrenone between 4 — 6 hours after administration of 50 mg spironolactone. The pharmacological activity of spironolactone, assessed simultaneously by alterations in fludrocortisone-induced urinary electrolyte changes, was slightly but not significantly reduced. The reductions in urinary canrenone excretion correlated with changes in the urinary log 10 Na/K ratio. The results suggest that canrenone may be actively secreted at the proximal renal tubule, and that secretion is blocked by ASA or its conjugates. This is a possible mechanism for the pharmacological interaction between ASA and spironolactone which has been described previously.

Paradoxical potassium excretion in response to aldosterone antagonists.

SummaryThe activity of two aldosterone antagonists in reversing the urinary electrolyte changes induced by the mineralocorticoid fludrocortisone was examined in healthy subjects. Between 2–10 h after treatment there were dose-related increases in sodium excretion and the urine log 10 Na/K ratio, but no significant changes in urine volume, potassium concentration, or potassium excretion. Between 12–16 h after treatment there were dose-related increases in urine sodium excretion and the log 10 Na/K ratio. Unexpectedly, there were significant dose-relatedincreases in potassium excretion despite significant dose-related reductions in urinary potassium concentration. The paradoxical increases in potassium excretion were attributed to dose-related increases in urine volume in the same period. These observations may explain the increased potassium excretion occasionally observed during clinical use of aldosterone antagonists and suggest that potassium excretion in man is influenced by the urine flow rate.

Bioassay of a new aldosterone antagonist and evaluation of a simple method of quantitative comparison

The renal antimineralocorticoid activity of single oral doses of a new aldosterone antagonist OH OPC(ME)‐K was compared to that of spironolactone in two studies in healthy men. OH OPC(ME)‐K reversed the urinary electrolyte response to fludrocortisone in the period up to 16 hr after treatment, but it was less potent than spironolactone on a weight basis. The best estimate of the relative potency of OH OPC(ME)‐K:spironolactone (derived from a simple protocol using equal single doses of the two drugs) was 0.60:1 (95% confidence limits 0.24:1 to 1.42:1), in good agreement with the estimate from a more complex three‐dose parallel‐line bioassay (0.61:1, 95% confidence limits 0.48:1 to 0.79:1). The results of simple single‐dose studies can be used, with certain assumptions, to provide a useful estimate of the relative potency of new aldosterone antagonists at an early stage of development.