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

(Z/E)-endoxifen([Z/E]-4-羟基-N-去甲基他莫昔芬)是(Z)-Tamoxifen的代谢物，(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，然后由肝脏中的II相酶通过硫化或葡萄糖醛酸化3，4，5结合为非活性形式。 一些研究表明，在接受他莫昔芬治疗的患者中，代谢形成受损与较差的临床结果相关。因此，美国国家癌症研究所(NCI)癌症预防部门(DCP)建议评估(Z/E)-endoxifen作为局部经皮治疗(LTT)预防乳腺癌的局部凝胶制剂的管理。使用这种制剂将允许将活性他莫昔芬代谢物直接输送到目标组织，从而减少全身暴露以及相关的子宫和血栓栓子风险，并消除代谢依赖。 为了支持(Z/E)-endoxifen凝胶的临床研究，DCP正在征求毒理学承包商的建议，以进行以下临床前研究。

(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.