Spironolactone: Diversity in Metabolic Pathways

Abstract

Several new hydroxylated and reduced metabolites of spironolactone [steroidal aldosterone antagonist] in the urine and feces of the rat, dog and [rhesus] monkey after 50 mg/kg oral administration of 22-14C-spironolactone were purified by preparative TCL and identified by comparing their chromatographic [TLC and GLC] and mass spectral characteristics with those of synthetic samples. Metabolites were divided into those in which the S of spironolactone was removed and those in which this S was retained. Canrenone (CAN) was the primary metabolite in the 1st class. It was further metabolized by 3 main pathways: opening of the .gamma.-lactone ring to canrenoic acid which was excreted as canrenoate ester glucuronide, hydroxylation to 15.alpha.-hydroxy-CAN, 15.beta.-hydroxy-CAN and 21-hydroxy-CAN, and reduction to 6,7-dihydro-CAN, 4,5.beta.,6,7-tetrahydro-CAN, 4,5.alpha.,6,7-tetrahydro-CAN, 3.beta.-hydroxy,4,5.alpha.-tetrahydro-CAN, 3.beta.-hydroxy,4,5.beta.,6,7-hexahydro-CAN and 3.alpha.-hydroxy,4,5.beta.,6,7-hexahydro-CAN. Metabolites in the 2nd class were previously identified S-containing compounds: 7.alpha.-sulfoxide-spirolactones (2 epimers), 7-.alpha.-sulfone-spirolactone, 6.beta.-hydroxy-thiomethyl analogue and 6.beta.-hydroxy-sulfoxide. Canrenoate ester glucuronide, 21-hydroxy-CAN (excreted as a conjugate) and S-containing metabolites were important in the monkey, while the reduced metabolites were important in the dog.