Identification of spironolactone metabolites in plasma and target organs of guinea pigs.

Spironolactone (SL) is a renal aldosterone antagonist that is used clinically in the treatment of hypertension and congestive heart failure. Among the side effects of the drug are degradation of cytochrome P-450 and inhibition of steroidogenesis in the testes. It has long been recognized that the effects of SL are mediated by metabolites of the drug, but questions remain about the identities of the active metabolites. Because tissue metabolites of SL had not previously been investigated, experiments were done to determine the identities of metabolites in target organs after SL administration to guinea pigs. Metabolites were identified by HPLC and MS. The major plasma metabolite was 7 alpha-thiomethyl-SL (TM) with smaller amounts of canrenone (CAN) and 7 alpha-thio-SL (TH) also present. In kidneys, TM also was the principal metabolite, but CAN was the only other compound consistently found. By contrast, in testes, substantial amounts of SL and TH were present in addition to TM and CAN. It is possible that local metabolism of SL contributes to the differences in metabolite profiles between plasma and target organs. Data also suggest that TM is principally responsible for the renal antimineralocorticoid effects of SL and support the purported role of TH in the degradation of testicular cytochrome P-450.