Paroxetine Mesylate

Paroxetine mesylate is a selective serotonin reuptake inhibitor that exerts its antidepressant effects primarily by blocking the serotonin transporter. However, in vivo evidence demonstrates that paroxetine also binds to the norepinephrine transporter at clinically relevant serum concentrations.
In rats treated with paroxetine via osmotic minipumps for one week, serum paroxetine concentrations greater than 100 ng/mL were positively correlated with increased Kd values for [³H]-nisoxetine binding to cortical membranes, indicating occupancy of the norepinephrine transporter. At [³H]-nisoxetine concentrations equivalent to 50 percent transporter occupancy in vehicle-treated rats, paroxetine-treated rats with serum concentrations between 100 and 500 ng/mL showed a 21 percent decrease in specific binding, while those with concentrations exceeding 500 ng/mL showed a 34 percent decrease. Ex vivo [³H]-norepinephrine uptake assays confirmed functional inhibition of the norepinephrine transporter. This dual action on both serotonin and norepinephrine transporters at higher therapeutic doses may underlie the broad therapeutic utility of paroxetine in mood and anxiety disorders beyond that explained by serotonin reuptake inhibition alone.

Fig. 1 Serum Paroxetine concentrations are positively correlated with the apparent Kd of [3H]-nisoxetine for the norepinephrine transporter. (Owens M J.; et al. 2000)

Paroxetine mesylate nanoemulsion was developed for direct nose-to-brain delivery to bypass first-pass metabolism and improve bioavailability. The oil-in-water nanoemulsion was prepared by spontaneous emulsification using Capmul MCM as oil phase, Solutol HS 15 as surfactant, and propylene glycol as co-surfactant. Transmission electron microscopy confirmed spherical droplets with mean diameter of 58.47 nm, polydispersity index of 0.339, and zeta potential of -33 mV. The optimized formulation showed 2.57-fold enhancement in permeation compared to paroxetine suspension. In Wistar rat models of depression, intranasal administration of the nanoemulsion significantly reduced immobility time in forced swimming test and restored glutathione and TBARS levels to near-normal values, demonstrating improved antidepressant efficacy through direct olfactory region delivery.

Fig. 2 Drug permeated per unit time from formulation P2 and Paroxetine suspension. (Pandey Y R.; et al. 2016)