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

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 g/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.This study was supported by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.