PRECLINICAL PREVENT TOXICOLOGY AND PHARMACOLOGY

（Z/E）-内昔芬（[Z/E]-4-羟基-N-去甲基他莫昔芬）是（Z）-他莫昔芬的代谢物，（Z）内昔芬可能是他莫昔芬大部分药理活性的原因1，2，3，4。内昔芬由细胞色素P450（CYP）3A 4和CYP 2D 6分两步形成，然后由肝脏中的II相酶通过硫酸化或葡萄糖醛酸化结合成非活性形式3，4，5。 一些研究表明，内昔芬代谢形成受损与他莫昔芬治疗患者的临床结局较差相关。因此，美国国家癌症研究所（NCI）癌症预防部（DCP）建议评估局部凝胶制剂中（Z/E）-内昔芬的给药作为局部透皮治疗（LTT）用于乳腺癌预防。使用该制剂将允许将活性他莫昔芬代谢物直接递送至靶组织，从而降低全身暴露和相关的子宫和血栓栓塞风险，以及消除代谢依赖性。 为了支持（Z/E）-内昔芬凝胶（NCI）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.