Influence of quinidine, cimetidine, and ketoconazole on the enantioselective pharmacokinetics and metabolism of metoprolol in rats

Authors

  • Vanessa Bergamin Boralli,

    1. Department of Clinical, Toxicologic, and Bromatologic Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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  • Eduardo Barbosa Coelho,

    1. Department of Internal Medicine, Discipline of Nephrology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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  • Vera Lucia Lanchote

    Corresponding author
    1. Department of Clinical, Toxicologic, and Bromatologic Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
    • Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Departamento de Análises Clínicas, Toxicológicas and Bromatológicas, Avenida do Café s.n. Campus da USP, 14040-903, Ribeirão Preto, SP, Brazil
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Abstract

Metoprolol is a β-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), α-hydroxymetoprolol (OHM) (Chiralpak® AD column), and metoprolol acidic metabolite (AODM) (Chiralcel® OD-R column) were determined by HPLC using fluorescence detection (λexc = 229 nm; λem = 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. Chirality 2009. © 2009 Wiley-Liss, Inc.

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