Spironolactone and canrenoate‐K: Relative potency at steady state

Abstract

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 fludrecortisone 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 attributed to the metabolite canrenone. The results at steady state are contrasted with those of a previously study comparing single doses of spironolactone and canrenoate-K.

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

“…Most clinical experience 1isWith spironolactone and the closely related compound, canrenoate potassium, which, on repeated dosing, have a common major active metabolite (Ramsay et al, 1977). However, another steroidal aldosterone antagonist, SC8109, was extensively studied in patients (Liddle, 1958;Slater, 1960;Gantt, 1961;Drill, 1962).…”

Spironolactone in thiazide‐induced hypokalaemia: variable response between patients.

“…Modem formulations of micronized spironolactone have satisfactory bioavailability (Clarke, Ramsay, Shelton, Tidd, Murray & Palmer, 1977), but the drug undergoes extensive and complex metabolism (Sadee, Dagcoiglu & Schroder, 1973;Karim, Zagarella, Hribar & Dooley, 1976). The major unconjugated metabolite canrenone is responsible for approximately 70% of the renal antimineralocorticoid activity of spironolactone at steady state (Ramsay, Asbury, Shelton & Harrison, 1977). Plasma canrenone concentrations vary fourfold in healthy men (Clarke et al, 1977) and fifteenfold in patients with heart failure and chronic liver disease (Sadee, Schroder, v. Leitner & Present address: University Department of Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF.…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…Canrenone itself is used as a drug, as well as an analog in which the lactone ring is open and dosed as the potassium salt (canrenoate). It is not entirely clear regarding all the entities' contributions to activity and whether activity is better related to plasma or urinary concentrations; however, canrenone has been estimated to contribute to 73% of the activity (Ramsay et al, 1977). While spironolactone and potassium canrenoate yield similar levels of canrenone, spironolactone is more potent, suggesting that other spironolactone metabolites may contribute to activity (Kojima et al, 1985;Peile, 1985).…”