P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood–brain barrier in vivo

摘要: P-glycoprotein (P-gp)-mediated brain efflux of xenobiotics is a well-known process, which may result in suboptimal target engagement and consequently reduced efficacy drugs exerting their therapeutic effects the central nervous system. In present study role P-gp transport across blood-brain barrier (BBB) was investigated with series newer antidepressants (levomilnacipran, vilazodone vortioxetine) control substrate (escitalopram) using knock-out (KO) competent wild-type (WT) mice. Brain plasma exposure time-courses were measured after an acute subcutaneous dose at steady-state obtained drug infusion by osmotic minipumps. Following dosing, brain-to-plasma KO/WT enhancement ratios ((AUCbrain ko/AUCplasma ko)/(AUCbrain WT/AUCplasma WT)) 5.8 (levomilnacipran), 5.4 (vilazodone), 3.1 0.9 (vortioxetine), respectively. At steady-state, assessment Kp,uu (unbound concentrations/unbound concentrations) revealed restriction distribution WT mice for all compounds except vortioxetine. Levomilnacipran exhibited most pronounced Kp,uu-value 0.038 increased to 0.37 KO Based on both data, results suggest that levomilnacipran, escitalopram are susceptible mediated BBB in vivo mice, whereas vortioxetine practically devoid being affected in vivo. The functional impact transport-controlling demonstrated cortical serotonin transporter occupancy vilazodone, 20-fold higher EC50 compared KOs.