| Abstrakt: |
The metabolic conversion of spironolactone (I) to canrenone (II) was investigated using a chemical model reaction by treatment of spironolactone in aqueous medium at pH 13. The dethioacetylation proceeds in two steps, i.e., a fast hydrolysis to the 7α-thiol function present in congeners VI and VI ( K=0.42 min), and a rate limiting step by elimination of HS yielding the 4,6-dien-3-one function present in canrenone (II) and canrenoate (III) ( K=0.13 h). The metabolic conversion of I to II was evaluated by intravenously injecting equimolar amounts of I, the 7α-thiol VI, II and III. Following injection of I, the only fluorigenic metabolites detectable were II, III, and an intermediate polar metabolite, which was identified by tlc and mass spectrometry as the 7α-thiol-17β-hydroxycarboxylic acid VI. The plasma t of I was 4 and 5 min, respectively, in two rats. The t of VI amounted to 8 and 12 min, respectively, and roughly corresponded to the formation rate canrenone (II). Injection of the 7α-thiol VI resulted in plasma concentrations of VI, II and III similar to those obtained from injection of I. It can be concluded that hydrolysis of the 7α-thioacetyl I to the 7α-thiol VI is a very rapid metabolic step, that the γ-lactone ring is in a rapid enzymatic equilibrium with the corresponding γ-hydroxylic acids, and that elimination of HS from VI yielding II is the overall rate limiting step in the metabolic conversion of I to II. The elimination of intravenous doses of H-I and H-III occurred predominantly by biliary excretion of polar conjugated metabolites (80 and 95%, respectively, of the dose over 12 h) followed by extensive enterohepatic cycling. Urinary excretion remained below 3% of the dose over 12 h in bile fistula rats. [ABSTRACT FROM AUTHOR] |
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