Altered drug-serum protein binding in the genetically obese Zucker rat.
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 alpha1-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 serum binding of the Sprague-Dawley rat more closely resembling the obese Zucker rat.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D003975:Diazepam / Q000097:blood; D005260:Female; D008954:Models, Biological; D009943:Organophosphorus Compounds; D004364:Pharmaceutical Preparations / Q000097:blood*; D010672:Phenytoin / Q000097:blood; D011433:Propranolol / Q000097:blood; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011924:Rats, Zucker; D013045:Species Specificity
D001798:Blood Proteins; D009943:Organophosphorus Compounds; D004364:Pharmaceutical Preparations; D010672:Phenytoin; D011433:Propranolol; D003975:Diazepam; C013320:tris(2-butoxyethyl) phosphate