Mechanistic modeling of drug elimination by the liver using local volume averaging method

Local volume averaging method and local mass (drug) equilibrium were used for developing a mathematical model for transient drug transport and elimination in the liver. Taking into account the liver porosity and tortuosity, physio-chemical properties of the drug, the drug effective diffusivity, dispersion, convection, local plasma-hepatocyte equilibrium and hepatocellular drug metabolism, the governing partial differential equation was developed and numerically solved to describe a transient drug transfer and elimination across the liver following intravenous (IV) administration. The predicted values of hepatic clearance and bioavailability had very good agreement with the reported observations for different drugs. Unlike the well-stirred, parallel tube and dispersion models of hepatic clearance, the proposed mechanistic model is able to predict the drug concentration gradient across the liver with time and position in very dynamic conditions associated with drug absorption process in the intestine.