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 l inearity of triamterene kinetics was not systematically tested. Moreov er, although triamterene is mostly applied concomitantly with thiazide -type diuretics the interaction of triamterene (TA) with hydrochloroth iazide (HCT) is subject to a controversial discussion. Therefore, the aim of this study was to examine the dose linearity of TA and the phar macokinetic and pharmacodynamic interaction of triamterene and hydroch lorothiazide. In the first study 10 healthy volunteers received 0, 12. 5, 25, 50, and 100 mg triamterene orally in a balanced crossover desig n. In the second study 0, 25, and 50 mg TA with 12.5, and 25 mg HCT, r espectively, were administered to 12 healthy volunteers. Urine volume and concentration of sodium, TA, hydroxytriamterene sulfate (OH-TA est er), and HCT were measured by flame photometry and thin-layer chromato graphy, respectively. The observation period for each treatment was 3 days and the drug was given on the second day. Sodium excretion was in creased by both drugs. Renal excretion of both TA and OH-TA ester seem ed to be reduced at higher doses. However, statistical evaluation reve aled no significant (p = 0.37, and p = 0.20, respectively) deviation f rom linearity. Renal excretion of HCT was not affected by TA and vice versa. However, renal excretion of OH-TA ester is significantly reduce d 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 pharmac okinetic interaction. The results support the hypothesis of a sequenti al nephron blockade for both drugs acting on different tubular segment s.