PHARMACOKINETICS OF SPIRONOLACTONE, CANRENONE AND CANRENOATE-K IN HUMANS

Equimolar doses of spironolactone (I), canrenone (II) and canrenoate-K (III) were given orally and III intravenously to 16 patients. Canrenoate-K (III) was rapidly and quantitatively absorbed from the gastrointestinal tract and bypassed the liver unchanged. The oral bioavailability of the lipophilic II to the central compartment was about 80% relative to III in one patient, which was calculated from the area under the plasma concentration-time curves of II. Spironolactone (I) was dethioacetylated to about 79% to canrenone (II) when judged by the plasma levels of II following oral administration of I and II to the same patient. Equimolar doses of spironolactone (I) and canrenoate-K (III) led to similar plasma levels of II 3 to 12 hours following oral administration, while the plasma levels of III differed in magnitude. The half-lives of II and III following doses of I-III ranged within 17 to 22 hours in the terminal log-linear phase of elimination from plasma in five patients. The half-life of radioactivity in plasma following an oral dose of 3H-III exceeded 50 hours. As measured by fluorescence assays, 14 to 24% of doses of I-III were excreted into the urine within five days and 33% of an oral dose of 3H-III within four days, as measured by radioactivity analysis. Nonfluorigenic metabolites accounted for 50% of the amount excreted into the urine over four days. A major part of the metabolism remains unknown.