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The investigations have been performed to determine the relative bioavailability of canrenon from Acelat 100 capsules in comparison with canrenon from a spironolactone standard preparation available on the German market. This was carried out by comparing the areas under the serum fluctuation curves after oral application of both preparations as well as by urine excretion extrapolated infinitely. The preparations were administered together with a standard breakfast. Subsequently up to 48 h blood was withdrawn from the Vena cubiti. According to a known method serum samples were analysed spectrophotometrically. The data obtained were fitted to an open two-compartment model with the RIP-procedure. The core of the program is a Gauss-Newton iteration (minimising the last squares). These are the results: By intraindividual comparison of the areas under the serum fluctuation curves of canrenon a relative bioavailability of 116.27% (s = 16.84) of canrenon from Acelat 100 could be calculated versus canrenon from the standard. Urine excretion, extrapolated infinitely, showed a 4% higher excretion of canrenon after application of Acelat 100 compared to standard. Both results are not significantly different in the range of biological scattering. The further pharmacokinetic parameters calculated were within the range of the literature available.

In a preliminary open bioequivalence investigation of orientating character (n =4) a single 100 mg dose of spironolactone (study I) led to maximum canrenone plasma levels (determined by HPLC) of 126.5 +/- 28.4 ng/ml (standard formulation 1) and 130 +/- 13.1 ng/ml (test formulation 2). The corresponding values for the sum of the fluorogenic metabolites were 418.9 +/- 43.5 ng (eq)/ml formulation 1 and 469.9 +/- 80.3 ng (eq)/ml formulation 2. A comparison of AUCs for both total fluorogenic metabolites and canrenone showed no marked differences. In a 2nd cross-over bioequivalence study with multiple dosing, mean minimum steady-state levels of 102.5 +/- 14 ng/ml (formulation 1) and 98.1 +/- 14.1 ng/ml (formulation 2) were obtained for canrenone, and 389 +/- 35.8 ng (eq)/ml (formulation 1) and 391.4 +/- 18.9 ng (eq)/ml (formulation 2) for total fluorescence. The AUCs for post-steady-state elimination, starting with the final spironolactone dose on day 10, were comparable. They were calculated to be 13226 +/-828 ng (eq)/ml . h (formulation 1) and 13858 +/- 651 ng (eq)/ml . h (formulation 2) for total fluorescence, and 3222 +/- 217 ng/ml (formulation 1) and 3167 +/- 195 ng/ml (formulation 2) for canrenone. Both spironolactone formulations can be considered as bioequivalent. The elimination half-lives (t 1/2) after a single 100 mg dose of spironolactone are (Study I) 16.4--19.1 h for canrenone and 13.6--14.0 h for the sum of the active (i.e., antagonistic to aldosterone) metabolites. Certain therapeutic conditions (e.g. multiple dosing of 100 mg spironolactone with tau = 12 h, Study II) can lead to slightly increased t 1/2 values for both canrenone (18.6--21.4 (h)) and total fluorogenic metabolites (15.8--16.9 (h)). The steady-state level for both formulations is reached by the third day of treatment.

The biological availability of spironolactone in two different galenic preparations (Spiro-Tablinen and Aldactone-100 Caps) was investigated in a single-blind, randomised, cross-over study in six healthy probands. The serum concentration of canrenone after oral intake of spironolactone (100 mg) was investigated in the steady state as well as the renal excretion of canrenone. There were no statistically significant differences between the two preparations either in the course of the serum concentration of canrenone or in the cumulative renal excretion.

Age-dependent changes in the pharmacokinetics of two diuretics, spironolactone and triamterene, were investigated in 20 geriatric patients with multiple diseases. Average plasma concentrations of canrenone (both determined by High-Performance-Liquid-Chromatography (HPLC) and a fluorimetric method) were significantly higher in geriatric patients compared with a younger control group of healthy volunteers (p less than 0,002). There was also a significant positive correlation between age (of the geriatric patients) and the area under the plasma concentration curve of canrenone. Plasma concentrations of canrenone (measured by HPLC after 120 hours) were closely correlated with number of red cells in the geriatric patients (p less than 0,01). Maximum plasma concentrations of triamterene and its pharmacologically active phase-II-metabolite were clearly higher in the geriatric patients when compared with a younger control group of healthy volunteers. Maximum plasma concentrations of the phase-II-metabolite were inversely correlated with diastolic blood pressure (p less than 0,01). Plasma levels of triamterene and its phase-II-metabolite in the older patients seem to be influenced not only renal perfusion pressure but also by uric acid levels.

By the US Food and Drug Administration spironolactone is regarded as a drug with problems related to bioavailability. A steady-state study was performed comparing the 50- and 100-mg formulations of two manufacturers with each other. Applying a fluorimetric method to both canrenone and canrenoate--the major biologically active metabolites of spironolactone--the two brands were compared in 11 volunteers for the 50 mg, and in 10 volunteers for the 100 mg dosage form.

An intraindividual comparative multiple-dose study (6 days) was carried out under controlled conditions on 10 healthy volunteers in order to establish the bioavailability of bendroflumethiazide (Bft; 3-benzyl-6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzoth iad iazine-1, 1-oxide), the sum of the fluorogenic metabolites of spironolactone (3-[3-oxo-7-alpha-acetylthio-17 beta-hydroxy-4-androstene-17-alpha-yl]-propionic acid-gamma-lactone) and canrenone, the main spironolactone metabolite from a fixed combination of Bft with spironolactone vs. the commercial preparations of the single drugs. Canrenone was assayed from plasma by high-performance liquid chromatography (HPLC) whereas Bft and the total aldosterone antagonistically acting spironolactone metabolites were determined fluorometrically. Both the fixed and the monosubstance formulation can be considered as bioequivalent for canrenone and the total fluorescence. Bft, in contrast, shows a reduced systemic availability of 61% when administered as the single drug formulation. A 2-compartment model was taken as the basis for the calculation of the steady-state plasma concentration curves and the pharmacokinetic parameters of Bft, canrenone and the sum of the fluorogenic spironolactone metabolites. Following oral multiple administration of 2.5 mg Bft (b.i.d.), the terminal elimination half-life, the steady-state volume of distribution and the total plasma clearance were determined to be 8.6-8.2 h, 0.88 l/kg and 269.4 ml/min, resp. In contrast to Bft, the AUC(120,tlast)-values for post-steady-state elimination, starting with the final spironolactone dose on day 6 were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

The autoradiographic localisation of H3-spironolactone in whole-body sections of mice is shown. The drug is enriched in the liver, bile-ducts and in the content of the small intestine, which probably indicates a biliary excretion.