PBPK Modeling of Metoprolol and Its Metabolites
Purpose: Develop a model describing absorption and pharmacokinetics of metoprolol and the formation and pharmacokinetics of its metabolites.
Methods: GastroPlus™ (Simulations Plus, Inc.) was used to fit the model describing absorption and pharmacokinetics of metoprolol and its metabolites. A physiologically-based pharmacokinetic (PBPK) model was used to describe the distribution and pharmacokinetics (DPK) of metoprolol along with the simultaneous DPK of its metabolites. The in vitro metabolism of metoprolol to its two major metabolites (α-hydroxy-metoprolol and Odemethylmetoprolol) measured in human liver microsomes  was used to describe the metabolic clearance of metoprolol and formation of the metabolites. The renal clearance of metoprolol was estimated using glomerular filtration rate and fraction unbound in plasma. The renal clearance of the final metabolites was fitted to match the amount of radioactive metabolites secreted in urine .
Population Approach Group in Europe (PAGE), June 18-20, 2008, Marseille, France
By Viera Lukacova, Walter S. Woltosz, Michael B. Bolger