Abstract
Tissue distribution and local targeting kinetics of PSC 833 (PSC), a multidrug resistance (MDR) modifier, were extensively studied in vitro, with human originated tumor cells, and in vivo, with tumor bearing mice. In vitro studies demonstrated that the membrane transfer and interaction with flux-carrier-protein are relatively rapid for PSC, and estimated an inhibitory constant (Ki) of 0.02 μg/ml using daunorubicin as substrate. In vivo distribution study also revealed the rapid drug distribution to normal and neoplastic tissues. These tissue distribution profiles were modeled by taking into account the time and dose-dependent plasma protein binding which was studied separately with an ex vivo technique. A physiologically-based pharmacokinetic (PBPK) model developed accordingly not only described globally the drug disposition in the whole body but also quantitatively characterized the extent of P-glycoprotein suppression efficacy at tumor site as well as brain exposure which increases sensitively to the increase in the blood concentration, resulting potential neurotoxicity. The present approach based on the PBPK model is considered helpful to optimize the safe and efficient use of the MDR modifier.
