Influence of chronic renal failure on stereoselective metoprolol metabolism in hypertensive patients

• Published in: Journal of clinical pharmacology Vol. 45; no. 12; p. 1422
• Main Authors: Cerqueira, Paula Macedo, Coelho, Eduardo Barbosa, Geleilete, Tufik José Magalhães, Goldman, Gustavo Henrique, Lanchote, Vera Lucia
• Format: Journal Article
• Language: English
• Published: England 01.12.2005
• Subjects: Adrenergic beta-Antagonists - blood; Adrenergic beta-Antagonists - pharmacokinetics; Adrenergic beta-Antagonists - urine; Adult; Antihypertensive Agents - blood; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - urine; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Debrisoquin - analogs & derivatives; Debrisoquin - pharmacokinetics; Debrisoquin - urine; Female; Humans; Hypertension - metabolism; Kidney Failure, Chronic - metabolism; Male; Metoprolol - pharmacokinetics; Middle Aged; Mutation; Stereoisomerism
• ISSN: 0091-2700
• DOI: 10.1177/0091270005281816

The influence of chronic renal failure on the stereoselective metabolism of rac-metoprolol was investigated in 15 hypertensive patients, 7 of them with chronic renal failure and 8 with normal renal function. They were treated with rac-metoprolol (200 mg) for 7 days. The patients of both groups presented stereoselectivity in metoprolol metabolism, favoring the formation of 1'R-alpha-hydroxymetoprolol (AUC(1(')R/1(')S)(0-24) approximately 2.5) and (R)-metoprolol acidic metabolite (AUC((S)/(R))(0-24) = 0.8), the latter resulting in the plasma accumulation of (S)-metoprolol (AUC((S)/(R))(0-24) = 1.2). Patients with chronic renal failure presented plasma accumulation of the 4 alpha-hydroxymetoprolol isomers and of both metoprolol acidic metabolite enantiomers. A 50% reduction in Cl(R) does not explain the 3- to 4-fold plasma accumulation of metoprolol acidic metabolite in this group, suggesting that other pathways of metoprolol elimination are affected in chronic renal failure in addition to renal excretion. Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite.