Titre du document / Document title

Pharmacokinetic- pharmacodynamic interactions of candesartan cilexetil and losartan

Auteur(s) / Author(s)

AZIZI M. ⁽¹⁾ ; CHATELLIER G. ⁽¹⁾ ; GUYENE T.-T. ⁽¹⁾ ; MENARD J. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Broussais Hospital Clinical Investigation Center, INSERM, and Assistance Publique des Hôpitaux de Paris, Paris, FRANCE

Résumé / Abstract

Background The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. Objective To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. Design and methods In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. Results The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 ± 96 mmHg/h) was significantly greater than that for placebo (-112 ± 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 ± 95 mmHg/h) or 50 mg losartan (-144 ± 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P < 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. Conclusions The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.

Revue / Journal Title

Journal of hypertension   ISSN 0263-6352   CODEN JOHYD3 

Source / Source

1999, vol. 17, n^o4, pp. 561-568 (29 ref.)

Langue / Language

Anglais

Editeur / Publisher

Lippincott Williams & Wilkins, Hagerstown, MD, ETATS-UNIS  (1983) (Revue)

Mots-clés anglais / English Keywords

Candesartan ; Angiotensin antagonist ; Losartan ; Arterial pressure ; Pharmacokinetics ; Drug interaction ; Biological activity ; Human ; Antihypertensive agent ;

Mots-clés français / French Keywords

Candésartan ; Antagoniste angiotensine ; Losartan ; Pression artérielle ; Pharmacocinétique ; Interaction médicamenteuse ; Activité biologique ; Homme ; Antihypertenseur ;

Mots-clés espagnols / Spanish Keywords

Candesartán ; Antagonista angiotensina ; Losartán ; Presión arterial ; Farmacocinética ; Interacción medicamentosa ; Actividad biológica ; Hombre ; Antihipertensivo ;

Localisation / Location

INIST-CNRS, Cote INIST : 20680, 35400008359763.0150