Intracellular Pharmacokinetics of Activated Drugs in a Prodrug–Enzyme–Ultrasound System: Evaluations on ZD2767P+CPG2+US

Abstract

Intracellular pharmacokinetics (PK) of activated drugs is a window to understanding the pharmacodynamics of prodrug−enzyme−ultrasound therapy. Herein PK of ZD2767D (i.e., activated drug) in the ZD2767P+CPG2+US system on A549, A549/DDP, SKOV3, and SKOV3/DDP cells were evaluated (A549/DDP and SKOV3/DDP were cisplatin-resistant sublines). The noncompartment model under extravascular input mode was deemed appropriate for evaluating drug level vs time curves; C max , AUC last , MRT last , V z , and Cl can reflect the PK feature, but t 1/2 , AUC inf , and MRT inf were irrational; higher accumulation and slower elimination characterized the PK mechanism of ZD2767P +CPG2+US; enhanced permeability and retention effect can be assessed with C max , AUC last , MRT last , and t last ; ultrasound equivalently modulated C max and AUC last in sensitive and resistant cells. The experimental design and dose proportionality were discussed.