title: Influence of chronic renal failure on stereoselective metoprolol metabolism in hypertensive patients.
abstract: 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.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil.
authors.forename: Paula Macedo
authors.initials: PM
authors.lastname: Cerqueira
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Tufik José Magalhães
authors.initials: TJ
authors.lastname: Geleilete
authors.forename: Gustavo Henrique
authors.initials: GH
authors.lastname: Goldman
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003647:Debrisoquin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics*; D008875:Middle Aged; D009154:Mutation; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; C012359:4-hydroxydebrisoquin; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D003647:Debrisoquin