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，其中 (Z) Endoxifen 可能负责他莫昔芬的大部分药理活性1,2,3 ,4. Endoxifen 由细胞色素 P450 (CYP) 3A4 和 CYP2D6 分两步形成，然后通过肝脏中的 II 相酶结合至失活。通过硫酸化或葡萄糖醛酸化形成3,4,5。 一些研究表明，内多昔芬代谢形成受损与接受他莫昔芬治疗的患者临床结果较差有关，因此，美国国家癌症研究所 (NCI) 癌症预防部门 (DCP) 提议评估 (Z/E) 的给药。 ）-内多昔芬作为局部透皮疗法（LTT）用于预防乳腺癌，使用该制剂可以将活性他莫昔芬代谢物直接递送至靶组织，从而减少全身暴露和相关子宫。和血栓栓塞风险，以及消除代谢依赖性。 为了支持 (Z/E)-endoxifen 凝胶的临床研究，NCI、DCP 正在寻求毒理学承包商的建议以进行以下临床前研究。