title: Differential metabolism of 3FDT and docetaxel in RLMs, rats, and HLMs.
abstract: 3FDT, an analog of docetaxel with a blocked metabolism at its 3'-N-tert-butyloxyl group with three fluorine atoms, exhibits more potent cytotoxicity than docetaxel both with human cancer cell line SK-OV-3 in vitro and with human non-small cell lung cancer A549 xenografts in vivo. To further develop pharmacodynamically and pharmacokinetically favorable fluorinated docetaxel analogs as anticancer agents, we chose 3FDT as the model compound to identify the metabolites of 3FDT in RLMs, rats, and HLMs and the cytochrome P450 enzymes responsible for the metabolism of 3FDT. Our findings indicated that the major metabolic site switched from the C3' appendage for docetaxel to the taxane ring for 3FDT, and the main metabolizing P450 enzymes switched from CYP3A to CYP3A4 and CYP2E1.
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chang
authors.affiliation: Research Institute for Liver Diseases (Shanghai) Co. Ltd., Shanghai 201203, China.
authors.forename: Zhuo-Han
authors.initials: ZH
authors.lastname: Hu
authors.affiliation: Pharmacological Evaluation Research Center, Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, China. Electronic address: qinyn11@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 201203, China. Electronic address: sunxunf@shmu.edu.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System
keywords: 3FDT; Anticancer agents; Cytochrome P450; Metabolites