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Physiological Metabolism Model

iDEA pkEXPRESS™ physiological Metabolism Model was designed and validated to predict the fraction dose absorbed into systemic circulation (FH) or bioavailability of potential drug compounds.  The Liver Flow modelsimulates first pass metabolism using the predicted absorption rate from the Absorption Model, protein binding, and metabolic stability of a compound. 


The metabolism model was optimized using internally generated in vitro data, a training set of literature and collaborator pharmacokinetic clinical data, and chemical structures.  The 82 drugs in the training set come from 37 different therapeutic classes and were selected to cover a broad range of KM, CLInt, protein binding, and extent of metabolism.  Other phamacokinetic models with explicit solutions, such as the Well-Stirred and Parallel-Tube model require the assumption of linear kinetics. 

These models often over predict the extent of metabolism when the metabolizing enzymes are saturated, which often occurs during the initial passage of drug through the liver.  In order to overcome this issue, the Metabolism Model incorporates the Michaelis-Menton equation to describe non-linear, saturating turnover kinetics.  By doing this, the model successfully predicts FH for compounds whether they demonstrate linear or non-linear turnover kinetics without overestimating first pass metabolism. 


The physiological metabolism model is based on Distributed Liver model (Pang, K. S. and Rowland, M., Pharmacokinet.Biopharm, 1977, 5:625-653).  This model (Figure 1)represents the liver as a number of parallel cylindrical tubes with metabolizing enzymes distributed uniformly around each tube.  The model is a numerical simulation of the flow and metabolism of drug through the physiologilcal model, and accounts for both linear and non-linear metabolic turnover. 


Blood from the portal vein, containing drug absorbed from the gastrointestinal tract, enters the tubes from the right side and exits into the hepatic vein, and systemic circulation, on the left.  As a drug moves down the length of the tubes, the concentration of the drug declines as it is metabolized by the enzymes at each section of the tubes.  A correlation relating the in vitro hepatocyte turnover data to the in vivo first pass metabolism ensures the correct amount of metabolism occurs as the drug travels through the simulation.

Characteristics of Compounds in the Metabolism Model


Vmax (umol/min)

Km (uM)

FH (%)

EH (%)

Caco-2 Permeability (cm/sec)

Solubility (mg/ml)

Absorption (%)






1.11 x 10-7








5.05 x 10-5