Effect of plasma protein binding on quinidine kinetics in the rabbit.
The relationship between the unbound fraction and kinetic parameters describing the disposition of quinidine in rabbits with a wide spread in protein binding values was examined. Both total and unbound quinidine concentrations followed two-compartment kinetics. The blood clearance of unbound quinidine, as well as the apparent volumes of distribution for both total and unbound quinidine, were correlated with the unbound fraction of the drug in plasma. No correlations were observed between the unbound fraction and the clearance of total quinidine or the fast and slow disposition rate constants of free and total drug. These observations are in agreement with the proposed models for elimination of drugs by the liver. They suggest, however, an interrelationship between binding to plasma proteins and binding to other proteins which is not taken into consideration in accepted models for apparent volume of distribution. Because unbound drug is the pharmacologically active species and clearance of unbound drug is the main determinant of unbound steady-state plasma concentrations, the measurement of protein binding of drugs with a high extraction ratio in the eliminating organ is essential for drugs with a narrow therapeutic index.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D008099:Liver / Q000098:blood supply*; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D011802:Quinidine / Q000378:metabolism*; D011817:Rabbits; D012039:Regional Blood Flow
D001798:Blood Proteins; D011802:Quinidine