R-fluoxetine Increases Extracellular DA, NE, As Well As 5-HT in Rat Prefrontal Cortex and Hypothalamus An in vivo Microdialysis and Receptor Binding Study

Abstract

The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S stereoisomers. In

A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

“…Unlike 19-F MRS, the serum samples obtained permitted measurement of the individual stereoisomers and their respective metabolites. At week 5, the compounds active at the reuptake pump (Rand S-fluoxetine and S-norfluoxetine) (Koch et al, 2002) accounted for 83, 29, and 37% of the serum drug/metabolite concentration for the racemate, 80 mg/day, and 120 mg/day of R-fluoxetine groups, respectively. As noted in Table 1, there were no medication group differences at baseline, but as expected, there were impressive racemate vs 80 mg/day and racemate vs 120 mg/day differences at week 5.…”

“…The primary metabolites of concern are R-and S-norfluoxetine. As described above, R-norfluoxetine is thought to be inactive at both the reuptake pump and the IID6 isoenzyme, while Snorfluoxetine is active at the reuptake pump and is a more potent inhibitor of the IID6 isoenzyme than its parent compound (Koch et al, 2002). Therefore, knowing the relative contribution of each of these chemical species to the MRS signal would permit a determination of the amount of active drug in the brain.…”

“…Racemic fluoxetine consists of two stereoisomers, R-and S-fluoxetine (Robertson et al, 1988), which are metabolized to R-and S-norfluoxetine, respectively (Jannuzzi et al, 2002). Both enantiomers of the parent compound are potent inhibitors of the serotonin reuptake pump, although R-fluoxetine also has modest affinity at the 5-HT2A and 5-HT2C receptors compared to S-fluoxetine (Koch et al, 2002;Owens et al, 2001). In contrast, the enantiomers of the metabolite norfluoxetine have more pronounced differences.…”

“…In contrast, the enantiomers of the metabolite norfluoxetine have more pronounced differences. S-norfluoxetine binds to the transporter with an affinity similar to R-and S-fluoxetine and is therefore regarded as an active metabolite (Koch et al, 2002). R-norfluoxetine has no affinity for the serotonin reuptake pump or other monoaminergic receptors and is therefore regarded as an inactive metabolite (Koch et al, 2002).…”

The promiscuity of the dopamine transporter: Implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes

“…A concentration of 10 μM fluoxetine was selected based on its common use in kinetics studies of 5-HT uptake inhibition (Asano et al, 1997, Martin et al, 2000, Pollier et al, 2000, Zhang et al, 2002, Fernandez et al, 2003. In an effort to achieve selective 5-HT uptake at SERT, a concentration of 0.05 μM paroxetine was selected, which is 200-fold higher than its K i at SERT (0.1 -0.4 nM; for review see Nemeroff & Owens, 2003) and about 20-fold lower than its K i at DAT (1.0 μM; Nemeroff & Owens, 2003;Owens et al, 2001, Koch et al, 2002. Kinetic analyses inform mechanistic evaluations of pharmacotherapeutic candidates as well as current pharmacotherapies.…”