Complications in assessing the hepatic first-pass component of bioavailability
Unit of Clinical Pharmacology, University of Sheffield, UK
Simcyp® has been a joint venture between the
The common PBPK models involving calculation of oral bioavailability are based on estimation of gut absorption (with or without components of gut first pass effect) and hepatic first pass effect. These models do not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned (or not partitioned) into blood cells, and plasma lipids. Recently, Berezhkovskiy  has investigated the influence of drug kinetics in blood on the calculation of oral bioavailability in linear pharmacokinetics and indicated that the traditional equation may considerably overestimate the true value of availability. As part of this presentation it would be indicated that the ability to predict changes in fraction unbound is a key component of estimating hepatic first pass effect (Fh) from iv data. This becomes even more important when two drugs are given together as it becomes an essential component of the prediction of the extent of drug - drug interactions, especially if other mechanisms of interaction, such as changes in enzyme activity, are occurring simultaneously.
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 Berezhkovskiy. Pharm Sci , 2006, 95:834–848