Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone

The pharmacokinetics of canrenone and 'total metabolites' after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and 'total metabolites' were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t_1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t_1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of 'total metabolites' after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of 'total metabolites' was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and 'total metabolites' were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.