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Influence of Gasoline Inhalation on the Enantioselective Pharmacokinetics of Fluoxetine in Rats
Author(s) -
Cardoso Juciane Lauren Cavalcanti,
Lanchote Vera Lucia,
Pereira Maria Paula Marques,
Capela Jorge Manuel Vieira,
Lepera José Salvador
Publication year - 2013
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.22136
Subject(s) - chemistry , enantiomer , fluoxetine , chromatography , pharmacokinetics , pharmacology , stereochemistry , biochemistry , serotonin , receptor , medicine
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 AUC 0‐∞ 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.