Chronopharmacokinetics of the antidepressant paroxetine: An in vitro and in vivo approach

Abstract

The circadian rhythm influences homeostatic functions such as sleep, physical activity and food intake as well as pharmacotherapy, namely pharmacokinetics.

To investigate the impact of the circadian rhythm on the pharmacokinetics of paroxetine, in vitro synchronized permeability studies were carried out in a tri-culture blood-brain barrier model. Paroxetine demonstrated lower apparent permeability when the cells were incubated at 24 h post-synchronization than at 36 h. Additionally, in vivo chronopharmacokinetic studies were performed in CD-1 female mice administered with paroxetine (5 mg/kg) by intranasal route in the early morning or evening. Paroxetine exposure in the brain was higher when it was administered at the beginning of the active phase (ZT13) compared with the rest phase (ZT1) (p < 0.001), probably owing to the lower levels of P-glycoprotein expressed in the brain at the active phase (p < 0.05). Since melatonin production depends on serotonin, its plasma concentrations were also assessed in vivo. The results demonstrated that melatonin concentrations increased 12 h after paroxetine nasal instillation at ZT13 (p < 0.05), but remained unchanged at ZT1, suggesting that the drug effect is influenced by administration time.

In conclusion, the circadian rhythm impacted the pharmacokinetics of paroxetine, especially its distribution into the brain, the target organ. This emphasizes the importance of the time of administration in antidepressant dosing, highlighting its relevance for future studies.