Impact of Extensive Plasma Protein Binding on the In Situ Hepatic Uptake and Clearance of Perampanel and Fluoxetine in Sprague Dawley Rats

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The main objective was to investigate the effect of albumin (ALB) and/or alpha-1-acid glycoprotein (AGP) on the hepatic clearance (CLh) of the drugs that bind, extensively, to both proteins.Isolated perfused livers from male Sprague Dawley rats (IPRL) were performed for perampanel (PER) and fluoxetine (FLU), using physiological solutions in four scenarios (n = 3 rats/scenario/drug): 1) without plasma proteins (WO), 2) with bovine ALB (40 g/L), 3) with bovine AGP (1 g/L), and 4) with mixture of both proteins (MIX).PER is poorly to moderately metabolized (hepatic extraction = 0.2–0.7), while FLU is highly metabolized (hepatic extraction = 0.8–0.99). The metabolic kinetics were fitted to the Michaelis-Menten model. For the PER, the parameters were Vmax = 90, 16.4, 86.1 and 16.9 (nmol/min/g liver) and unbound Km = 17, 1.7, 38.3 and 1.4 (μM) for the scenarios WO, with ALB, with AGP and with MIX, respectively. As for FLU, the parameters were Vmax = 65.5, 18.5, 33.8 and 12.2 (nmol/min/g liver) and unbound Km = 1.5, 0.03, 0.14 and 0.0466.31 (μM) in all four scenarios, respectively.In conclusion, a protein-mediated hepatic uptake likely occurred only at low concentrations for both drugs (i.e., therapeutic concentrations) in the presence of plasma proteins (except for the scenario of PER with AGP).