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

Author(s)

Cavalcanti Cardoso, Juciane Lauren ^[1] ; Lanchote, Vera Lucia ^[1] ; Marques Pereira, Maria Paula ^[1] ; Vieira Capela, Jorge Manuel ^[2] ; Lepera, Jose Salvador ^[3]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-05508 Sao Paulo - Brazil

^[2] Univ Estadual Paulista, Inst Quim, Dept Quim Fis, BR-14801902 Araraquara, SP - Brazil

^[3] Univ Estadual Paulista, Fac Ciencias Farmaceut Araraquara, Dept Principios Ativos Nat & Toxicol, BR-14801902 Araraquara, SP - Brazil

• Document type: Journal article
• Source: CHIRALITY; v. 25, n. 3, p. 206-210, MAR 2013.
• Web of Science Citations: 3

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 25:206210, 2013. (c) 2013 Wiley Periodicals, Inc. (AU)

• FAPESP's process: 09/17532-0 - Influence of chronic exposure to automotive fuels in the activity of CYP3A, CYP2C9 and CYP2D in rats treated with chiral drugs
• Grantee: Jose Salvador Lepera
• Support Opportunities: Regular Research Grants