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

Tinghe Yu; Xinya Li; Tianran Yu; Mengjie Chen; Yong Sun; Rui Ran

doi:10.1021/acsmedchemlett.4c00071

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

ACS Med Chem Lett. 2024 Apr 4;15(5):739-745. doi: 10.1021/acsmedchemlett.4c00071. eCollection 2024 May 9.

Authors

Tinghe Yu¹, Xinya Li¹, Tianran Yu², Mengjie Chen¹, Yong Sun³, Rui Ran¹

Affiliations

¹ Laboratory of Obstetrics and Gynecology, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
² Yangjiaping High School, Chongqing 400039, China.
³ Department of Emergency Medicine, Sichuan Mianyang 404 Hospital, Mianyang 621000, China.

PMID: 38746880
PMCID: PMC11089658 (available on 2025-05-09)
DOI: 10.1021/acsmedchemlett.4c00071

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.