New insights into the pharmacokinetics of spironolactone

Abstract

Four healthy men took a single oral dose of 200 mg spironolactone after a standardized breakfast. Blood samples were drawn until 24 hours after dosing. A specific HPLC method was used to determine the serum concentrations of spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and canrenone. Pharmacokinetic parameters were derived from the serum concentration-time course of each compound. Spironolactone, 7 alpha-thiomethylspirolactone, and canrenone are known to have antimineralocorticoid activity in man. Our study demonstrated that: (1) 7 alpha-Thiomethylspirolactone is the main metabolite of spironolactone after a single oral dose as judged by the AUC(0-24) and the maximum concentration; and (2) unchanged spironolactone was detected in serum, with a maximum concentration at 1 hour and detectable levels up to 8 hours after dosing. Our findings are contrary to the widely accepted belief that spironolactone is metabolized too rapidly to be detected in serum after oral dosing and that canrenone is the principal metabolite of spironolactone.

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

“…In the dose range 1-10 mol/L, compatible with the concentrations reached by the drug in the serum after oral administration, [43][44][45][46] canrenone is able to inhibit cell growth and chemotaxis induced by PDGF without affecting basal cell proliferation and motility. To elucidate which step(s) of PDGF signaling are affected by canrenone, the effects of this drug on the downstream pathways induced by this growth factor were investigated.…”

Spironolactone and Canrenone Inhibit UGT2B7-Catalyzed Human Liver and Kidney Microsomal Aldosterone 18β-Glucuronidation: A Potential Drug Interaction

“…Thus, calculation of hepatic input concentration is not possible. However, this parameter will exceed the combined plasma concentration of spironolactone and canrenone, which has been reported to be approximately 1 M after a single oral dose of 200 mg (Overdiek et al, 1985). At present, the inhibitory potential of other metabolites of spironolactone, such as 7␣-thiomethylspironolactone and 6␤-hydroxy-7␣-thiomethylspironolactone, whose combined concentrations in plasma are almost double those of spironolactone and canrenone (Overdiek et al, 1985), is unknown.…”

“…However, this parameter will exceed the combined plasma concentration of spironolactone and canrenone, which has been reported to be approximately 1 M after a single oral dose of 200 mg (Overdiek et al, 1985). At present, the inhibitory potential of other metabolites of spironolactone, such as 7␣-thiomethylspironolactone and 6␤-hydroxy-7␣-thiomethylspironolactone, whose combined concentrations in plasma are almost double those of spironolactone and canrenone (Overdiek et al, 1985), is unknown. Although the extent of an inhibitory interaction for a drug cleared by the liver in vivo may be predicted from the K i and hepatic input concentration of inhibitor (Miners et al, 2010), the majority of ALDO 18␤-glucuronidation (approximately 80%) occurs in the kidney.…”

Stimulation of Microsomal Spironolactone Metabolism by Reduced Glutathione

“…Prior investigations demonstrated that the deacetylation of SP to 7a-thio-SL, catalyzed by tissue esterases [ 13], was the first step in the production of biologically active metabo lites of the drug [6][7][8][9][10][11][12], In the adrenal cortex and testes, subsequent metabolism of 7a-thio-SL by the steroid 17a-hydroxylase leads to the formation of reactive products that effect P450 degradation and inhibition of steroido genesis [5,6,16]. The relative rates of the enzymatic steps required for SP activation suggested that deacetylation was rate-limiting for P450 destruction in adrenal microsomes [6], Thus, factors affecting this reaction could have significant impact on the actions of SP.…”

“…Side effects of SP include inhibi tion of steroidogenesis in the testes and adre nal cortex, caused by cytochrome P450 degra dation in both organs [5,6], Many if not all of the effects of SP appear to be mediated by metabolites of the drug [6][7][8][9][10][11]. Prior investigations have established that the deacetylation of SP to 7a-thiospirolactone (7a-thio-SL) is an obligatory first step in the activation of the drug [6][7][8][9][10][11][12][13]. 7a-Thio-SL is then converted to other metabolites that are responsible for the therapeutic actions and side effects of SP.…”