IGF::OT::IGF PRECLINICAL PREVENT TOXICOLOGY AND PHARMACOLOGY

IGF::OT::IGF 临床前预防毒理学和药理学

• 批准号: 9360345
• 负责人: DAVID MCCORMICK, PH.D. DABT
• 金额: $ 153.19万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2018-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360345
• 关键词: Adverse effects; Biological Availability; Bone Marrow Cells; Breast Cancer Prevention; CYP2D6 gene; CYP3A4 gene; Cavia; Cells; Clinical; Clinical Research; Contractor; Delayed Hypersensitivity; Dependence; Dermal; Division of Cancer Prevention; Dose; Enzymes; Formulation; Gel; Gene Mutation; In Vitro; Liver; Mammalian Cell; Metabolic; Miniature Swine; N-desmethyltamoxifen; National Cancer Institute; Oral; Outcome; Patients; Pharmacology and Toxicology; Phase; Phototoxicity; Plasma; Rattus; Recovery; Risk; Tamoxifen; Tissues; Toxic effect; Toxicology; albino mouse; in vivo; pre-clinical; preclinical study; prevent; sulfation

(Z/E)-Endoxifen ([Z/E]-4-hydroxy-N-desmethyltamoxifen) are metabolites of (Z)-tamoxifen, with (Z) endoxifen likely being responsible for the majority of tamoxifen’s pharmacologic activity1,2,3,4. Endoxifen is formed in two steps by cytochrome P450 (CYP) 3A4 and CYP2D6, and then conjugated by phase II enzymes in the liver to inactive forms by sulfation or glucuronidation3,4,5. Some studies have shown that impaired metabolic formation of endoxifen is associated with worse clinical outcomes for tamoxifen-treated patients. As such, the National Cancer Institute (NCI), Division of Cancer Prevention (DCP) is proposing to evaluate administration of (Z/E)-endoxifen in a topical gel formulation as localized transdermal therapy (LTT) for breast cancer prevention. Use of this formulation would allow delivery of the active tamoxifen metabolite directly to the target tissue, thereby reducing systemic exposure and associated uterine and thromboembolic risks, as well as eliminating metabolic dependence. To support clinical studies with (Z/E)-endoxifen gel, NCI, DCP is seeking proposals from the Toxicology Contractors to conduct the following preclinical studies.

（Z/E）-Endoxifen （[Z/E]-4-羟基- n -去甲基他莫昔芬）是(Z)-他莫昔芬的代谢物，(Z) endoxifen可能是他莫昔芬的大部分药理活性的原因。Endoxifen由细胞色素P450 (CYP) 3A4和CYP2D6分两步形成，然后由肝脏II期酶通过硫酸化或葡萄糖醛酸化偶联成无活性形式3,4,5。