title: Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™.
abstract: DZNep is a potential epigenetic drug, and exerts potent anti-proliferative and pro-apoptotic effects on broad-spectrum carcinomas via disruption of the EZH2 pathway. Antitumor studies on DZNep have been stuck in the preclinical phase because of the lack of information about its integral pharmacokinetic (PK) properties. To circumvent this problem, we extensively investigated the disposition characteristics of the DZNep in rats. By incorporating the disposition data across species into a whole-body physiologically based pharmacokinetic (PBPK) models using the GastroPlus(TM) software, we simulated human PK properties of DZNep and determined whether DZNep could be developed for human cancer therapy. Firstly, DZNep was found to cause nephrotoxicity in a dose-dependent manner in rats and its safe dose was determined to be 10mg/kg. DZNep showed a short plasma elimination half-life (1.1h) in rats, a low protein binding in plasma (18.5%), a low partitioning to erythrocyte (0.78), and a low intrinsic hepatic clearance in rats and humans. There was extensive tissue distribution and predominant renal excretion (80.3%). The simulated rat PBPK model of DZNep was well-verified with satisfactory coefficients of determination for all the tested tissues (R(2)>0.781). The simulated human PBPK model successfully identified that intravenous administration of DZNep at appropriate dosing regimen could be further developed for human non-small cell lung carcinoma treatments. The present findings provide valuable information regarding experimental or in silico PK characteristics of DZNep in rats and humans, which is helpful to guide future studies of DZNep in both preclinical and clinical phases.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive, Singapore 117543, Singapore; Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lee
authors.affiliation: Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, A(*)STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Guilin Medical University, 109 Huancheng Road, Guilin 541004, PR China; Department of Obstetrics & Gynaecology, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore. Electronic address: xqduan9288@yahoo.com.
authors.forename: XiaoQun
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive, Singapore 117543, Singapore. Electronic address: eli.w.y.chan@gmail.com.
authors.forename: Eli
authors.initials: E
authors.lastname: Chan
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; C048460:3-deazaneplanocin; D000241:Adenosine
keywords: 3-Deazaneplanocin A; GastroPlus; Human non-small cell lung carcinoma; Physiologically based pharmacokinetic models