Is it Possible to Differentiate between Angiotensin II Type 1 (AT1) Receptor Blockers in Normotensive Volunteers?

Abstract

Variability of blood pressure responses to inhibition of the renin-angiotensin system is influenced by factors inherent in the patient, such as renin status, and by drug-specific factors, such as pharmacokinetics. The pharmacokinetic-pharmacodynamic interactions of two doses of candesartan cilexetil, which is an ester prodrug of the insurmountable angiotensin II type 1 (AT 1 ) receptor blocker candesartan, were compared with those of the standard dose of losartan in normotensive volunteers whose renin status was controlled by mild sodium depletion. In a double-blind, placebo-controlled crossover study, the effects of single oral doses of candesartan cilexetil, 8 mg and 16 mg, and losartan, 50 mg, were compared for 24 h in 16 healthy individuals pretreated with a single 40-mg dose of furosemide. Mean blood pressure was recorded by repeated measurements using the oscillometric method. In addition, measurements were made of plasma active renin, angiotensin I and angiotensin II, and plasma levels of candesartan and EXP-3174, the active metabolites of candesartan cilexetil and losartan, respectively, were determined by high-performance liquid chromatography and correlated to pharmacodynamic changes. The large interindividual variability of EXP-3174 levels in subjects who received losartan revealed a significant correlation between active renin and peak drug levels ( r = 0.77, n = 16, p < 0.01). Such a correlation was not found within either group of individuals who received candesartan cilexetil, because of lower interindividual pharmacokinetic variability. A dose-response relationship was found between plasma renin and candesartan when both doses of candesartan cilexetil were analysed. The pharmacodynamic effects of a single oral dose of candesartan cilexetil, 16 mg, were superior to those of candesartan cilexetil, 8 mg, and losartan, 50 mg (see Table). This conclusion has been confirmed by the results of a parallel-group, dose-determination study performed in hypertensive patients. The less variable pharmacokinetic-pharmacodynamic interaction for candesartan cilexetil than for losartan could account for the smooth 24-h reduction in blood-pressure found in patients treated with candesartan cilexetil. These results suggest not only that AT 1 -receptor antagonists can be differentiated, but that they will not be equally useful in clinical practice where, in contrast to clinical research, clear evidence is more difficult to obtain because of variability in renin status. © 2000, Informa UK Ltd All rights reserved: reproduction in whole or part not permitted. All rights reserved.