Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design

► Mechanistic insights can be derived by comparing liver microsome and hepatocyte stability. ► Liver microsomes and hepatocytes give comparable intrinsic clearance for CYP mediated clearance. ► Liver microsomes give lower metabolic rate than hepatocytes for non-CYP mechanisms. ► Comparison of intrinsic clearance from liver microsomes and hepatocytes cannot easily identify hepatic uptake or efflux transporter substrates. ► Whether passive permeability will limit hepatocyte metabolism is dependent on the metabolic rate.