ANALYSIS OF METABOLITES - A NEW APPROACH TO BIOEQUIVALENCE STUDIES OFSPIRONOLACTONE FORMULATIONS

The aldosterone antagonist spironolactone undergoes extensive and comp lex biotransformation. For investigation of bioequivalence of 2 oral s pironolactone formulations, Spironolacton 50 Heumann and Aldactone 50, the pharmacokinetics and bioequivalence of the parent drug and 2 pred ominant active metabolites, canrenone and 7 alpha-thiomethylspirolacto ne, were determined in a 2-way crossover study in 24 young healthy mal e volunteers after multiple oral dosing of 100 mg once daily, Plasma s amples were measured by a newly developed HPLC assay and individual ph armacokinetic parameters of the 3 compounds were calculated by use of noncompartmental techniques, Statistical analysis was performed by ANO VA and nonparametric methods, Spironolactone was rapidly cleared from plasma. Therefore, only C-ss,C-max and t(ss,max) were determined. Conc erning C-ss,C-max bioequivalence was found with 90% classical shortest confidence interval ranging from 80.7 - 112.4%. The intrasubject vari ability for C-ss,C-max was determined to be 28.1%, Higher and persisti ng concentrations were observed for the metabolites, For canrenone 90% classical shortest confidence intervals were calculated as 95.4 - 105 .0% for AUC(ss,tau) as 92.9 - 105.8% for C-ss,C-max, and as 89.1 - 106 .3% for peak trough fluctuation (PTF). In the case of 7 alpha-thiometh ylspirolactone the values were 84.2 - 103.0% for AUC(ss,tau). 77.0 - 9 8.6% for C-ss,C-max, and 85.0 - 100.4% for PTF. For t(ss,max) nonparam etric 90% confidence intervals were determined as 0.00 to 1.50 h for s pironolactone and canrenone and as -0.50 to 1.00 h for 7 alpha-thiomet hylspirolactone, The intraindividual variability was below 30% for all pharmacokinetic parameters in the case of the metabolites. Thus, bioe quivalence of the test and the reference formulation can be concluded. The study suggests the inclusion of parent compound and metabolites f or bioequivalence testing of spironolactone formulations. Intraindivid ual subject variability was clearly diminished by investigating bioequ ivalence under steady-state conditions.