Protein binding and hepatic clearance: studies with tolbutamide, a drug of low intrinsic clearance, in the isolated perfused rat liver preparation.

The influence of altered drug binding on the hepatic elimination of tolbutamide, a drug of low intrinsic clearance, and on the formation of its metabolite, hydroxytolbutamide, was examined under linear conditions at steady state in the isolated in situ single-pass perfused rat liver preparation, with perfusate flow fixed at 15 ml/min. The fraction of tulbutamide unbound in the perfusate was varied (from 0.06 to 1.0) by either varying the perfusate concentration of albumin or using albumin of different animal species. The intrinsic clearance of tolbutamide varied fourfold between preparations (0.08-0.36 ml/min/g liver). Within each preparation the data were normalized to observations with a perfusate containing no protein. Both the extraction ratio (and clearance) of tolbutamide and the fraction of tulbutamide appearing as hydroxytolbutamide in effluent perfusate, a measure of hepatic metabolism, were directly proportional to the fraction of tolbutamide unbound in the perfusate.