Misuse of the Well-stirred Model of Hepatic Drug Clearance

The “well-stirred” model of hepatic drug clearance was first proposed by Gillette and established by Rowland et al. and Wilkinson and Shand. In the form that it is commonly used, net hepatic drug clearance based on whole-blood drug concentration is derived as a function of hepatic blood flow, the free fraction of drug in blood, and the intrinsic metabolic clearance in the liver based on unbound drug concentration. This assumes that the drug is distributed instantly and homogenously throughout liver water and that the unbound concentrations in plasma and liver water are identical. Effectively, this means that drug distribution into the liver is perfusion-limited with no diffusion delay and that no active transport systems are involved. The latter possibilities have generally been disregarded in most applications.

Author(s): Jiansong Yang, Masoud Jamei, Karen Rowland Yeo, Amin Rostami-Hodjegan, Geoffrey Tucker

Year: March 1, 2007