[Pharmacokinetics of isosorbide dinitrate examined by physiologically-based pharmacokinetic model]

To make a physiologically-based pharmacokinetic model of isosorbide dinitrate (ISDN), the author infused ISDN at 1, 10, 30 micrograms.kg-1.min-1 into anesthetized rabbits and measured concentrations of ISDN and its metabolites (2-ISMN and 5-ISMN) in plasma and in the brain, liver as well as fat tissue. There was the accumulation of ISDN in the brain and fat tissue. There was no significant difference in concentrations of ISDN between the plasma and liver, or in concentrations of its metabolites among plasma, and the tissues of the brain, liver and fat. Using these informations, the author constructed a physiologically-based pharmacokinetic model to human and estimated values were compared with observed values to determine the validity of the model. There was no remarkable differences between the estimated values and observed values. This suggests the validity of the model. The plasma concentrations of ISDN estimated by this model, showed a linear increase (Y = 25 X) with the infusion rate less than 6.0 micrograms.kg-1.min-1. The accumulation of ISDN, especially in the brain was suggested by this model.