[Reconstruction of drug dispositions in vivo from in vitro studies based on physiological pharmacokinetic modeling: from low-molecular weight drugs to polypeptide compounds].

I initially reviewed successful attempts of us and others to reconstruct in vivo drug dispositions from in vitro biochemical parameters (representing the plasma binding and hepatic metabolism). Despite these successes, however, recent evidence suggests that several factors, which have been overlooked so far, should be also taken into consideration to facilitate more reliable predictions. Those include; (i) possible existence of diffusional barrier (membrane limited tissue distribution), (ii) uneven distribution of metabolizing enzymes along the blood flow path in the liver, and (iii) the so called protein-mediated transport mechanism. The details of each factor have been discussed mainly based on our recent observations. The studies have been also extended to the analysis of pharmacokinetics of polypeptide hormones. The kinetic analysis of receptor-mediated endocytosis (RME) of polypeptides has been focused on, on the basis of the observations of the kinetics of epidermal growth factor (EGF) in the liver. The experimental systems include the in vitro isolated hepatocytes, perfused rat liver, and in vivo system, and the kinetic parameters representing the interaction of EGF with the cell surface receptors have been compared among the experimental systems.