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 thein vivo plasma concentration range. The blood-to-plasma concentration ratio (C _b/C _p) of quinidine also showed a concentration dependence. The steady-state volume of distribution (V _ss) determined over the plasma concentration range from 0.5 to 10 μg/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 thein 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 usingin vitro plasma protein binding and theC _b/C _p of quinidine. The tissue binding parameters were estimated fromin vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.