Relationship of Plasma Aldadiene Levels and Antimineralocorticoid Effects of Spironolactone in the Laboratory

Abstract

7should be looked for in such patients, since, if present, its correction might prolong life so that measures directed toward the underlying process of endotoxin shock could be effective.Summary. An immediate and progressive fall in blood glucose level occurs in CC14treated guinea pigs given a lethal dose of bacterial endotoxin. The hypoglycemia is evidently due to a decrease in rate of hepatic glucose production. Maintenance of the blood sugar level appears to prolong survival but does not alter the extreme susceptibility of these animals to endotoxin. Hypoglycemia should be looked for in patients with severe liver disease who develop gram-negative bac-teremia, since if uncorrected it could render all other therapeutic measures ineffective.Oral administration of spironolactone,* a steroidal spirolactone ( 1 ) and an antagonist of the renal electrolyte effects of mineralocorticoids (2), produces measurable plasma concentrations of a fluorogenic, A6-metabolite (3), 3-(3-0x04 7P-hydroxy-4,6-androstadien-17~yl)propanoic acid lactone( 1 ) or aldadiene. Such data on plasma aldadiene have been applied in study of gastrointestinal absorption with various pharmaceutical preparations of spironolactone (3-7). I n both experimental animals and man, data have suggested a correlation of aldadiene titers with renal electrolyte manifestations after spironolactone administration(4,7). However, as aldadiene obtained synthetically also possess antimineralocorticoid properties ( 1,8), an important question relates to relative influence of the A6-metabolite on renal properties of spironolactone. As one approach, therefore, spironolactone and aldadiene were examined * 3 -( 3 -0xo-7a-ace tylthio-1 7p-hydroxy-4-androsten-17a-yl) propanoic acid lactone ; AldactoneB is the trademark of G. D. Searle and Co. for brand of spironolactone. comparatively in rats and dogs for plasma aldadiene levels and urinary electrolyte effects; some data believed to be pertinent to the question are summarized below.Material and methods. In rats (175-225 g) , spironolactone or aldadiene was orally administered concurrently with 12 pug of deoxycorticosterone acetate (DCA) subcutaneously, as solutions of corn oil. Four-hour samples of urine were collected in metabolism cages (4 rats/cage) in one series of animals for Na and K determination. Antimineralocorticoid activity of the spirolactones was assessed by reversal of the urinary Na/K response to DCA according to previously described procedures ( 2 ) . DCA alone induces Na retention and K loss, to produce thereby a reduction in the ratio of urinary Na/K. Other rats treated identically were sacrificed under ether at 1, 2, 3 and 4 hours after treatment, and blood specimens from the abdominal aorta collected in heparinized tubes using a plastic cannula. Plasma was separated by centrifugation for aldadiene analysis. Trained female mongrel dogs (14-19 kg)

Relative potency of prorenoate and spironolactone in normal man

“…The mean and SEM results in the 12 subjects for sodium excretion, potassium excretion, Na/K ratio, log 10 10 Na/K, and urine volume are shown in Table I. This table also shows the significance levels for tests of linearity of the log dose-response trends, for the slope of the log dose-response trends, and for tests of parallelism of the log dose-responses of the two drugs.…”

“…In the early stages of evaluation of prorenoate, we wished, for safety reasons, to observe the effects of single doses of the drug before proceeding to repeated dosing. Kagawa and his coworkers 10,11 have shown that dose-response curves can be obtained using single doses of spirolactones in laboratory animals, and that this method of bioassay yields valid estimates of relative potency for these drugs. We 17 and others 20 have shown that the procedure of Ross 18 can be adapted to allow testing of single doses of aldosterone antagonists in normal man.…”

Canrenone—the Principal Active Metabolite of Spironolactone?

“…The two drugs must have a relative potency or, if this assumption is incorrect, the hypothesis that canrenone is responsible for the activity of both drugs must be rejected. (Kagawa et al, 1964). These workers treated rats and dogs with spironolactone and canrenone at doses which yielded similar levels of canrenone in plasma, and simultaneously measured the potency of the compounds in reversing the renal effects of deoxycorticosterone acetate.…”

“…The 7a-acetylthio substituent is removed completely from 80% of the administered dose (Sadee, Dagcioglu & Schr6der, 1973) yielding canrenone (other names: aldadiene, SC-9376) (Figure 1) as the principal non-conjugated metabolite in plasma. Canrenone is active as a mineralocorticoid antagonist in animals (Kagawa, Bouska & Anderson, 1964) and has been proposed as the principal pharmacologically active agent after administration of spironolactone to man (Sadee, Dagcioglu & Schr6der, 1972).…”

Comparison of single and divided daily dose spironolactone in the control of hypertension [letter]

“…From a study of subjects receiving spironolactone who had reached a steady state, Ramsay et al (1977) concluded that canrenone was the principal active metabolite of spironolactone. Conversely, in assessing the antimineralocorticoid activity of a single dose of spironolactone it has been shown that spironolactone was significantly more potent than predicted from the plasma canrenone levels both in human subjects (Ramsay et al, 1976) and animals (Kagawa, Bouska & Anderson, 1964). Furthermore, with a more selective chromatographic assay for canrenone (Dahlof et al, 1979;Ashbagen et al, 1979) the contribution of canrenone to the antimineralocorticoid effect of spironolactone is substantially lower than previously assumed from the fluorimetric method of Gochman & Gantt (1962).…”