[Pharmacokinetic studies and bioavailability of bendroflumethiazide in combination with spironolactone]

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)