Spironolactone: Diversity in Metabolic Pathways

Abstract

1. Several new hydroxylated and reduced metabolites of spironolactone in the urine and faeces of the rat, dog and monkey after 50 mg/kg oral administration of [22-14C]spironolactone were purified by preparative t.l.c. and identified by comparing their chromatographic (t.l.c. and g.l.c.) and mass spectral characteristics with those of synthetic samples.2. Metabolites were divided into those in which the sulphur of spironolactone was removed and those in which this sulphur was retained.3. Canrenone (CAN) was the primary metabolite in the first class. It was further metabolized by three main pathways: (1) opening of the y-lactone ring to canrenoic acid which was excreted as canrenoate ester glucuronide (2) hydroxy-lation to 15α-hydroxy-CAN, 15β-hydroxy-CAN and 21-hydroxy-CAN and (3) reduction to 6,7-dihydro-CAN, 4,5β,6,7-tetrahydro-CAN, 4,5α,6,7-tetra-hydro-CAN, 3β-hydroxy, 4,5α-tetrahydro-CAN, 3β-hydroxy,4,5β,6,7-hexahydro-CAN and 3α-hydroxy,4,5β,6,7-hexahydro-CAN.4. Metabolites in the second class were the previously identified sulphur-containing compounds: 7α-sulphoxide-spirolactones (two epimers), 7α-sulphone-spirolactone, 6β-hydroxy-thiomethyl analogue and 6β-hydroxy-sulphoxide.5. Canrenoate ester glucuronide, 21-hydroxy-CAN (excreted as a conjugate) and sulphur-containing metabolites were important in the monkey while the reduced metabolites were important in the dog.