Hepatic elimination of drugs with concentration-dependent serum protein binding.

For a drug with concentration-dependent serum protein binding, the unbound fraction of drug decreases during the drug elimination process. The clearance of the drug at a given blood flow rate is lower than would be expected from the observed unbound fraction in venous blood from a noneliminating organ. Based on both the "well-stirred" and "parallel tube" models, simulations demonstrated that consideration of concentration-dependent binding during drug elimination is important when the intrinsic clearance is higher than the blood flow and when the unbound drug concentration is much greater than the dissociation equilibrium constant of the binding complex.