Difference in metabolic profile of potassium canrenoate and spironlactone in the rat: Mutagenic metabolites unique to potassium canrenoate

The metabolic fates of potassium canrenoate (PC) and spironolactone (SP) were compared for the rat in vivo and in vitro. PC was metabolized by rat hepatic S9 to 6 alpha , 7 alpha - and 6 beta , 7 beta -epoxy-CAN. The beta -epoxide was further metabolized to its 3 alpha - and 3 beta -hydroxy derivatives as well as its glutathione (GSH) conjugate. Both 3 alpha - and 3 beta -hydroxy-6 beta , 7 beta -epoxy-CAN were shown to be direct acting mutagens in the mouse lymphoma assay, whereas 6 alpha , 7 alpha - and 6 beta , 7 beta -epoxy-CAN were not. These mutagenic metabolites, their precursor epoxides and their GSH conjugates were not formed from SP under identical conditions. The above findings appear to be due to inhibition of metabolism of CAN formed from SP by SP and/or its S-containing metabolites, since the in vitro metabolism of PC by rat hepatic microsomes was appreciably reduced in the presence of SP.