title: Dose-dependent pharmacokinetics of diflunisal in rats: dual effects of protein binding and metabolism.
abstract: The purpose of this study was to define the dual effects of saturable metabolism and saturable protein binding on the pharmacokinetics of diflunisal. Steady-state diflunisal concentration and its unbound fraction were examined in seven groups of rats to determine the relationships of infusion rate, concentration and total and unbound clearances. The total body plasma clearance decreased initially and then went up as the concentration of diflunisal increased, whereas the intrinsic clearance of unbound drug decreased with increasing concentration. The former is a consequence of saturable metabolism as well as saturable protein binding; the latter is a consequence of saturable metabolism. The fraction of unbound diflunisal increased with concentration. The biliary excretion data of ester and ether glucuronide suggested that both the ester and ether glucuronidation processes are capacity-limited, although the enzyme system for ether glucuronide has a lower Km and capacity than the system responsible for the ester glucuronidation.
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D004061:Diflunisal / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005965:Glucuronates / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008433:Mathematics; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012459:Salicylates / Q000378:metabolism*; D013997:Time Factors
chemical_list: D005965:Glucuronates; D011506:Proteins; D012459:Salicylates; D004061:Diflunisal