PHARMACOKINETICS AND PHARMACODYNAMICS OF RAMIPRIL AND PIRETANIDE ADMINISTERED ALONE AND IN COMBINATION

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combinati on were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramipril increased slightly (from 11.9 to 14.8 ng/ml, an d from 6.39 to 8.96 ng/ml, respectively) as did the area under the pla sma concentration-time curve of ramipril (0-4 h) and ramiprilat (0-24 h) (from 15.8 to 19.8 ng.ml(-1).h, and from 63.4 to 74.6 ng.ml(-1).h, respectively). The urinary excretion of ramiprilat also rose (from 6.8 2 to 7.73% of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ra mipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and t he concentration-response relationship for the inhibition of plasma AC E activity were not affected by piretanide. The peak plasma concentrat ion of piretanide was somewhat reduced (from 285 to 244 ng/ml) followi ng simultaneous treatment with ramipril. No other pharmacokinetic para meter was affected. Piretanide increased urine flow, and sodium, chlor ide and potassium excretion, especially during the first 2 hours follo wing administration. These pharmacodynamic parameters were not affecte d by ramipril.Thus, simultaneous administration of single oral doses o f ramipril and piretanide caused modest changes in the peak and averag e plasma concentrations of both drugs, which did not lead to detectabl e alterations in the pharmacodynamic parameters measured in healthy vo lunteers.