PHARMACOKINETICS OF SPIRONOLACTONE, CANRENONE AND CANRENOATE-K IN HUMANS

¹ Department of Clinical Pharmacology and Department of Cardiology, Klinikum Steglitz, School of Medicine, Free University of Berlin, and Clinical Pharmacology and Pharmacokinetics Section, Schools of Medicine and Pharmacy, University of Southern California, Los Angeles, California

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.

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