Altered Drug–Serum Protein Binding in the Genetically Obese Zucker Rat

Abstract

Drug–serum protein binding was evaluated in genetically obese Zucker rats, their lean littermates, and lean Sprague–Dawley rats. The free fraction (fp) of phenytoin was significantly higher in the obese rat (fp=0.177) compared to its lean littermate (fp=0.136), apparently due to displacement by free fatty acids. Conversely, diazepam and propranolol fp values were decreased in the obese Zucker rat (fp=0.107 and fp=0.122, respectively) compared to the lean Zucker rat (fp=0.140 and fp=0.174, respectively). Evidence strongly suggests that the increased binding of propranolol was not due to elevations in the serum concentrations of α1-acid glycoprotein (as is the case in the human obese population). Rather, the decreased fp for both diazepam and propranolol was a result of increased lipoprotein partitioning. Strain differences between the lean Zucker rat and lean Sprague–Dawley rat were also evident, with the serum binding of the Sprague–Dawley rat more closely resembling the obese Zucker rat.