Mechanistic Studies on the Disposition of Farnesol with Single and Multiple Dosin

金合欢醇单次和多次给药的处置机制研究

• 批准号: 7104030
• 负责人: THOMAS J COOK
• 金额: $ 7.7万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-16 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104030
• 关键词: cancer prevention; colorectal neoplasms; death; neoplasm /cancer; pharmacokinetics; tissues

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer deaths accounting for 10% of all cancer-related deaths in the United States. Despite a relative decline in colorectal cancer death rates in recent years, colorectal cancer remains a serious public health issue. Effective colorectal cancer prevention strategies and agents would therefore provide substantial health and societal benefits. Recent attempts at using conventional drugs as chemoprevention agents have been hampered because of serious systemic side effects. In particular, concerns about the cardiovascular toxicity of COX-2 inhibitors have prompted the cancellation of the "APPROVe" and "ARC" cancer prevention trials and will likely impact future prevention studies with conventional drugs. Clearly there is a need for identifying effective cancer prevention agents with a wider safety margin. Many cancer prevention agents isolated from foods have wide safety margins such as curcumin, sulforaphane, and perillyl alcohol. Theoretically, the systemic exposure to a colorectal cancer preventive agent may not be required since an orally administered compound will achieve its highest concentration at the desired site of action, i.e., the lumen of the gastrointestinal tract. Therefore, since systemic toxicity is intimately associated with the blood levels in the general circulation, i.e., pharmacokinetics or toxicokinetics, an ideal colorectal cancer prevention agent would attain high local concentrations in the target gastrointestinal tissues but exhibit limited to no systemic exposure. This localized delivery concept is a key component to the observed preventive effects and lack of toxicity of curcumin, which attains high concentrations in the gastrointestinal tract but has negligible oral bioavailability based on the parent compound. Identifying other compounds with curcumin-like properties would provide alternatives or potential combination agents for colorectal cancer prevention modalities. One potential candidate is farnesol, an isoprenoid phytochemical with observed preclinical chemopreventive activity in several cancer models including colorectal cancer. In particular, farnesol exhibited impressive preclinical in vivo chemopreventive activity in the azoxymethane - aberrant crypt foci (AOM-ACF) model in Fisher F344 rats by two independent research groups, one of which was co-authored by the two consultants on this grant. Furthermore, preliminary pharmacokinetic studies from our laboratory demonstrate that farnesol is rapidly and extensively metabolized upon oral administration of 14C-farnesol to Sprague-Dawley rats suggesting negligible systemic bioavailability. Therefore, the goals of this proposal are to further delineate the pharmacokinetics of farnesol, to characterize the gastrointestinal tissue disposition of the compound, and to determine the intestinal permeability and metabolism of farnesol in Fisher F344 rats, the strain used in AOM:ACF studies. Our hypothesis is that the pharmacokinetics and intestinal/colonic disposition of farnesol will ultimately determine its in vivo activity as a colorectal cancer prevention agent. To test this hypothesis and pursue the project goals, we propose to pursue the following Specific Aims: SA1: Determine the pharmacokinetics, oral bioavailability and gene expression effects of farnesol after acute administration and after 28 days of dosing in Fisher F344 rats. SA2: Determine the intestinal disposition and intestinal tissue kinetics of farnesol in Fisher F344 rats.

描述（由申请人提供）：结直肠癌是美国第二大癌症死亡原因，占所有癌症相关死亡的10%。尽管近年来结直肠癌死亡率相对下降，但结直肠癌仍然是一个严重的公共卫生问题。因此，有效的结直肠癌预防策略和药物将提供巨大的健康和社会效益。由于严重的全身副作用，最近使用常规药物作为化学预防剂的尝试受到阻碍。特别是，对COX-2抑制剂的心血管毒性的担忧已经促使“APPROVe”和“ARC”癌症预防试验的取消，并可能影响未来常规药物的预防研究。很明显，我们需要找到安全范围更广的有效防癌药物。从食品中分离出来的许多防癌剂都有很大的安全范围，如姜黄素、萝卜硫素和紫苏醇。从理论上讲，可能不需要全身暴露于结直肠癌预防剂，因为口服给药的化合物将在期望的作用部位，即胃肠道的管腔中达到其最高浓度。因此，由于全身毒性与全身循环中的血液水平密切相关，即药代动力学或毒代动力学，理想的结直肠癌预防剂应在目标胃肠道组织中达到较高的局部浓度，但表现出有限的或无全身暴露。这种局部给药概念是姜黄素观察到的预防作用和缺乏毒性的关键组成部分，姜黄素在胃肠道中达到高浓度，但基于母体化合物的口服生物利用度可以忽略不计。确定具有姜黄素样特性的其他化合物将为结直肠癌预防方式提供替代或潜在的联合药物。一个潜在的候选者是法尼醇，一种异戊二烯类植物化学物质，在包括结直肠癌在内的几种癌症模型中具有观察到的临床前化学预防活性。特别值得一提的是，法尼醇在两个独立的研究小组（其中一个由该基金的两位顾问共同撰写）在Fisher F344大鼠的偶氮甲烷异常隐窝灶（AOM-ACF）模型中表现出令人印象深刻的临床前体内化学预防活性。此外，我们实验室的初步药代动力学研究表明，经Sprague-Dawley大鼠口服14c -法尼醇后，法尼醇被迅速而广泛地代谢，这表明系统生物利用度可以忽略不计。因此，本研究的目的是进一步描述法尼醇的药代动力学，表征该化合物的胃肠道组织配置，并确定法尼醇在AOM:ACF研究中使用的菌株Fisher F344大鼠的肠道通透性和代谢。我们的假设是，法尼醇的药代动力学和肠道/结肠处置将最终决定其作为结直肠癌预防剂的体内活性。为了验证这一假设并实现项目目标，我们建议追求以下具体目标：SA1：确定法尼醇在Fisher F344大鼠急性给药和给药28天后的药代动力学、口服生物利用度和基因表达影响。SA2：测定法尼醇在Fisher F344大鼠肠道内的分布和肠组织动力学。