Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats.
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%).
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil.
Juciane Lauren Cavalcanti
JL
Cardoso
Vera Lucia
VL
Lanchote
Maria Paula Marques
MP
Pereira
Jorge Manuel Vieira
JM
Capela
José Salvador
JS
Lepera
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004347:Drug Interactions; D005473:Fluoxetine / Q000097:blood / Q000493:pharmacokinetics*; D005742:Gasoline / Q000009:adverse effects*; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D018687:Antidepressive Agents, Second-Generation; D005742:Gasoline; D005473:Fluoxetine