Analysis of nonlinear tissue distribution of quinidine in rats by physiologically based pharmacokinetics

Abstract

The nonlinear tissue distribution of quinidine in rats was investigated by a physiologically based pharmacokinetic model. Serum protein binding of quinidine showed a nonlinearity over the in vivo plasma concentration range. The blood-to-plasma concentration ratio (Cb/Cp) of quinidine also showed a concentration dependence. The steady-state volume of distribution (Vss) determined over the plasma concentration range from 0.5 to 10 micrograms/ml was 6.0 +/- 0.45 L/kg. The tissue-to-plasma partition coefficient (Kp) of muscle, skin, liver, lung, and gastrointestinal tract (GI) showed a nonlinearity over the in vivo plasma concentration range of quinidine, suggesting saturable tissue binding. The concentration of quinidine in several tissues and plasma was predicted by a physiologically based pharmacokinetic model using in vitro plasma protein binding and the Cb/Cp of quinidine. The tissue binding parameters were estimated from in vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.