title: Influence of quinidine, cimetidine, and ketoconazole on the enantioselective pharmacokinetics and metabolism of metoprolol in rats.
abstract: Metoprolol is a beta-blocker and its racemic mixture is used for the treatment of hypertension. In the present study we investigated the influence of CYP2D and CYP3A on the stereoselective metabolism of metoprolol in rats. Male Wistar rats (n = 6 per group) received racemic metoprolol (15 mg/kg) orally, with or without pretreatment with the CYP inhibitor ketoconazole (50 mg/kg), cimetidine (150 mg/kg), or quinidine (80 mg/kg). Blood samples were collected up to 48 h after metoprolol administration. The plasma concentrations of the stereoisomers of metoprolol, O-demethylmetoprolol (ODM), alpha-hydroxymetoprolol (OHM) (Chiralpak AD column), and metoprolol acidic metabolite (AODM) (Chiralcel OD-R column) were determined by HPLC using fluorescence detection (lambda(exc) = 229 nm; lambda(em) = 298 nm). CYP3A inhibition by ketoconazole reduced the plasma concentrations of ODM and AODM and favored the formation of OHM. CYP2D and CYP3A inhibition by cimetidine reduced the plasma concentrations of OHM and AODM and favored the formation of ODM. The inhibition of CYP2D by quinidine reduced the plasma concentrations of OHM and favored the formation of ODM. In conclusion, the results suggest that CYP3A is involved in the formation of ODM and CYP2D is involved in the formation of AODM.
authors.affiliation: Department of Clinical, Toxicologic, and Bromatologic Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Vanessa Bergamin
authors.initials: VB
authors.lastname: Boralli
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005215:Fasting; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000037:antagonists & inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D015394:Molecular Structure; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D002927:Cimetidine; D008790:Metoprolol; D011802:Quinidine; D007654:Ketoconazole