PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION OF SINGLE DOSES OF VALSARTAN AND ATENOLOL

Objective: Valsartan (V), a specific inhibitor of the angiotensin II r eceptor subtype, AT(1), has been developed for treatment of hypertensi on. Combination therapy with a beta-adrenoceptor blocking agent might be considered in cases with insufficient efficacy of V alone. Therefor e, an interaction trial was performed to evaluate the effects of co-ad ministration of V on the pharmacokinetics of atenolol (A), and vice ve rsa, and to monitor the pharmacodynamic response of plasma angiotensin II (ANG II) concentrations and plasma renin activity (PRA), as well a s of heart rate and blood pressure, under resting and exercise conditi ons. Methods: Twelve healthy, normotensive, male volunteers aged 23-46 years were treated with single doses of either 160 mg V or 100 mg A a lone, or with both drugs in combination (V + A) according to a three-p eriod crossover design. Plasma concentrations of V and A were determin ed using HPLC with fluorimetric and UV detection, respectively, and co ncentration-time profiles were established over 24 h. Plasma ANG II co ncentrations and PRA were monitored using specific radioimmunoassays. Heart rate and blood pressure were measured at rest and during exercis e on a cycle ergometer at a workload of 2.5 W/kg(-1). Results: For V, mean AUC and C-max were slightly higher when A was co-administered, th e ratios of log transformed values being 1.13 and 1.22 for AUC((0-inf) ) and C-max, respectively. For A, mean AUC and C-max were slightly low er when the drug was given in combination with V. The ratios of log-tr ansformed values in this case were 0.90 and 0.92, respectively. The sh arp increase in plasma ANG II concentrations and PRA, induced,by admin istration of V, was significantly attenuated when the drug was combine d with A. In the first 12 h after drug intake, heart rate and systolic blood pressure at rest were significantly decreased when V and A were co-administered compared with treatment with V alone. V given alone d id not influence heart rate or systolic blood pressure during exercise , whereas A alone and V + A led to a significant reduction in those va riables. Adverse experiences reported after A and V + A could be expla ined by the high degree of beta-adrenoceptor blockade resulting from t he administration of A. Conclusions: Go-administration of single doses of V and A does not modify the pharmacokinetics of the two drugs to a clinically relevant degree. With respect to pharmacodynamics; a singl e dose of A attenuates the increase in plasma ANC; II and PRA in respo nse to a single dose of V: and V has no effect on the hemodynamic resp onse to exercise. The combined treatment with single doses of 160 mg V and 100 mg A has some additive effects on resting blood pressure in h ealthy, normotensive subjects.