Bioequivalence Assessment of Two Formulations of Spironolactone in Chinese Healthy Male Volunteers

The bioavailability of a new spironolactone ((7α, 17α)-7-(acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone, CAS 52-01-7) formulation (test) was compared with a commercially available original formulation (reference) of the drug in 20 Chinese healthy male volunteers, aged between 21 and 27. The trial was designed as an open, randomized, single blind two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 100 mg spironolactone as a test or reference formulation with a 7-day washout period between the two formulations. The plasma concentrations of spironolactone and its active metabolite canrenone (CAS 976-71-6) were analyzed by a sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) method. The pharmacokinetic parameters included AUC 0–t , AUC 0–∞ , C max , t 1/2 , and T max . Values of AUC 0–t demonstrate nearly identical bioavailability of spironolactone from the examined formulations. The AUC 0–12 of spironolactone was 148.35 ± 39.5 and 144.39 ± 53.02 ng • h/ml for the test and reference formulation, respectively. The AUC 0–60 of the metabolite canrenone was 1873.36 ± 318.10 and 1911.28 ± 355.60 ng h/ml for test and reference formulation, respectively. The maximum plasma concentration (C max ) of spironolactone was 48.34 ±21.16 ng/ml for the test and 47.40 ± 23.40 ng/ml for the reference product and the C max of the metabolite was 122.90 ± 27.70 and 123.35 ± 27.29 ng/ml for the test and reference product, respectively. No statistical differences were observed for C max and the area under the plasma concentration-time curve for both spironolactone and its active metabolite canrenone. 90% confidence limits calculated for C max and AUC from zero to infinity (AUC 0–∞ ) of spironolactone and its metabolite were included in the bioequivalence range (80%−125% for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for spironolactone and its main active metabolite canrenone.