Pharmacokinetics and pharmacodynamics of triamterene and hydrochlorothiazide and their combination in healthy volunteers.

Although triamterene has been in clinical use for over 30 years, the linearity of triamterene kinetics was not systematically tested. Moreover, although triamterene is mostly applied concomitantly with thiazide-type diuretics the interaction of triamterene (TA) with hydrochlorothiazide (HCT) is subject to a controversial discussion. Therefore, the aim of this study was to examine the dose linearity of TA and the pharmacokinetic and pharmacodynamic interaction of triamterene and hydrochlorothiazide. In the first study 10 healthy volunteers received 0, 12.5, 25, 50, and 100 mg triamterene orally in a balanced crossover design. In the second study 0, 25, and 50 mg TA with 12.5, and 25 mg HCT, respectively, were administered to 12 healthy volunteers. Urine volume and concentration of sodium, TA, hydroxytriamterene sulfate (OH-TA ester), and HCT were measured by flame photometry and thin-layer chromatography, respectively. The observation period for each treatment was 3 days and the drug was given on the second day. Sodium excretion was increased by both drugs. Renal excretion of both TA and OH-TA ester seemed to be reduced at higher doses. However, statistical evaluation revealed no significant (p = 0.37, and p = 0.20, respectively) deviation from linearity. Renal excretion of HCT was not affected by TA and vice versa. However, renal excretion of OH-TA ester is significantly reduced when HCT is administered concomitantly. The renal excretion rate of sodium can be described by a common Emax model when the effects of the excretion rates of both TA and HCT are additive. It is concluded that the pharmacokinetics of TA is linear within the tested dose range and that pharmacodynamic additivity of HCT and TA is not due to a pharmacokinetic interaction. The results support the hypothesis of a sequential nephron blockade for both drugs acting on different tubular segments.