Structureactivity Relations And Pharmacological Profile

Paroxetine is a phenylpiperidine derivative chemically unrelated to any other antidepressant (Bourin et al. 2001) (Figure 15-1). As noted above, it has been traditionally codified with the SRI class of drugs and is indeed the most potent inhibitor of the serotonin transporter (5-HTT) within this group of compounds (Frazer 2001). By comparison, sertraline has about one-half and fluoxetine has only one-tenth the affinity of paroxetine for the human 5 HTT (Owens et al. 1997). Positron emission tomography (PET) reveals that 85%-100% of 5-HTT binding sites are occupied in the amygdala and midbrain following 20- to 40-mg daily doses of paroxetine in human subjects (Kent et al. 2002; Meyer et al. 2001). Paroxetine-induced antagonism of the 5-HTT is prolonged following single-dose administration, and transporter binding is maintained for up to 14 days after 4 weeks of treatment in rodents, suggesting that it dissociates slowly from the 5-HTT binding site (Magnussen et al. 1982; Thomas et al. 1987).

FIGURE 15-1. Chemical structure of paroxetine.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

Data from both humans and rodents, using the transfected human norepinephrine transporter (NET), have revealed that paroxetine is the most potent inhibitor of the NET among drugs classified as SRIs. Despite its relatively high affinity for the NET, paroxetine has a higher affinity for the 5-HTT (Finley 1994). Ex vivo experiments in rats demonstrated a 21% and 34% inhibition of the NET within the central nervous system (CNS) at serum concentrations of 100-500 ng/mL and >500 ng/mL, respectively (Owens et al. 2000). Results from an ex vivo study of patients with depression demonstrated substantial NET antagonism at serum concentrations attained with paroxetine IR dosages of 40 mg/day and higher (Gilmor et al. 2002) (Figure 15-2). These results have recently been replicated in depressed patients in a high-dose, forced-titration protocol comparing paroxetine CR dosages of 12.5 and 75 mg/day with venlafaxine XR dosages of 75-375 mg/day. Both medications produced dose-dependent inhibition of the 5-HTT and NET. Maximal 5-HTT inhibition for paroxetine and venlafaxine was 90% and 85%, respectively, whereas maximal NET inhibition for the two drugs was 33% and 61% (Owens et al. 2008). Such data reflect the inhibitory activity of both medications at the NET and 5-HTT within the CNS. The utility of ex vivo studies is best understood with respect to bioavailability. Paroxetine, which is highly protein bound, must pass through the blood-brain barrier in order to interact with the NET and thereby contribute to the antidepressant effect of the drug (Frazer 2001). Because the ex vivo studies utilize transfected cells in tissue culture exposed to patient sera, only free drug that is not protein bound is available to interact in the NE uptake assay. These results can therefore be extrapolated to pharmacological effects in the CNS. Whether the NET antagonism observed in these ex vivo studies has clinical significance in terms of additional efficacy in comparison with drugs that solely block 5-HT reuptake will need to be further studied.

FIGURE 15-2. Norepinephrine and serotonin uptake inhibition versus serum paroxetine concentration.

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