title: Effect of contrasted sodium diets on the pharmacokinetics and pharmacodynamic effects of renin-angiotensin system blockers.
abstract: Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.
authors.affiliation: Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. michel.azizi@egp.aphp.fr
authors.forename: Michel
authors.initials: M
authors.lastname: Azizi
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Beny
authors.initials: B
authors.lastname: Charbit
authors.forename: Grégoire
authors.initials: G
authors.lastname: Wuerzner
authors.forename: Séverine
authors.initials: S
authors.lastname: Peyrard
authors.forename: Eric
authors.initials: E
authors.lastname: Ezan
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: Joël
authors.initials: J
authors.lastname: Ménard
mesh_terms: D000293:Adolescent; D058671:Adrenergic beta-1 Receptor Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001262:Atenolol / Q000008:administration & dosage / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D002318:Cardiovascular Diseases / Q000178:diet therapy* / Q000188:drug therapy / Q000378:metabolism; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D015592:Immunoradiometric Assay; D008297:Male; D017257:Ramipril / Q000008:administration & dosage / Q000493:pharmacokinetics; D012016:Reference Values; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012982:Sodium, Dietary; D013777:Tetrazoles; D001262:Atenolol; D012083:Renin; D017257:Ramipril; C081643:candesartan
keywords: atenolol; candesartan; pharmacodynamics; pharmacokinetics; ramipril; sodium; valsartan