Influence of Gasoline Inhalation on the Enantioselective Pharmacokinetics of Fluoxetine in Rats

Authors

  • Juciane Lauren Cavalcanti Cardoso,

    1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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  • Vera Lucia Lanchote,

    1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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  • Maria Paula Marques Pereira,

    1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil
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  • Jorge Manuel Vieira Capela,

    1. Departamento de Físico-Química, Instituto de Química, Universidade Estadual Paulista, Brazil
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  • José Salvador Lepera

    Corresponding author
    1. Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas de Araraquara, Universidade Estadual Paulista, Brazil
    • Correspondence to: José Salvador Lepera, Faculdade de Ciências Farmacêuticas de Araraquara, Universidade Estadual Paulista, Rodovia Araraquara Jaú, Km 1, Campus da UNESP, 14801-902 Araraquara, SP, Brazil. E-mail: leperajs@fcfar.unesp.br

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ABSTRACT

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (–)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC(+)-(S)/(–)-(R) = 1.68). In animals exposed to gasoline, we observed an increase in AUC0-∞ for both enantiomers, with a sharper increase seen for the (–)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC(+)-(S)/(–)-(R) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (–)-(R)-fluoxetine enantiomer (55% vs. 30%). Chirality 25:206–210, 2013. © 2013 Wiley Periodicals, Inc.

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