In vitro–in vivo extrapolation of hepatic clearance: Biological tools, scaling factors, model assumptions and correct concentrations

Abstract

Although the measurement of metabolite formation or substrate depletion in in vitro systems, from recombinant enzymes to tissue slices, is a relatively routine task, there are a number of more or less unresolved issues in the extrapolation of the enzymatic intrinsic clearance into hepatic metabolic clearance. Nominal concentrations of the drug added to the incubation system are not necessarily the concentration the transporter or the metabolizing enzyme sees. In addition, peculiarities of incubation set-ups should be assessed. Unbound drug fractions (concentrations) in the in vitro system itself should be measured or estimated for the appropriate assessment of enzymatic intrinsic clearance. In addition, blood and/or plasma concentrations to be encountered in the in vivo situation should be measured or estimated for the extrapolation. Extrapolation always means making a number of assumptions and the most important of these, such as scaling factors from recombinant enzymes, microsomes or hepatocytes to the mass unit of the liver, liver weight, blood flow, and distribution volume amongst others, and so on, should be explicitly stated and included in the extrapolation process. Despite all the above-mentioned reservations the in vitro–in vivo extrapolation of metabolic clearance seems to be a useful and mostly fairly precise tool for predicting the important pharmacokinetic processes of a drug.

Key Words::

• Hepatic clearance extrapolation
• scaling factors
• extrapolation of in vitro data
• human liver
• microsomes
• homogenates
• hepatocytes
• slices
• recombinant enzymes
• in vitro incubation