Drug concentrations in mouse brain at pharmacologically active doses of fluoxetine enantiomers

The i.p. injection of R-fluoxetine into mice at doses of 1-10 mg/kg led to higher concentrations of the desmethyl metabolite, R-norfluoxetine, in whole brain than was true for S-fluoxetine. R-Norfluoxetine, but not S-norfluoxetine, concentrations predominated over those of the parent drug at 7-24 hr after injection of the corresponding fluoxetine enantiomer. The more rapid N-demethylation of R-fluoxetine, and the relative inactivity of R-norfluoxetine as a serotonin uptake inhibitor compared with S-norfluoxetine, may explain the earlier report that R-fluoxetine is less potent than S-fluoxetine in antagonizing p-chloroamphetamine depletion of brain serotonin in mice. In the present study, a 10 mg/kg, i.p., dose of S-fluoxetine completely prevented p-chloroamphetamine given 24 hr later from depleting brain serotonin, whereas R-fluoxetine offered no protection at this time.