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

描述（由申请人提供）：结直肠癌是癌症死亡的第二大原因，占美国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实质性的健康和社会效益。由于严重的全身性副作用，最近尝试使用常规药物作为化学预防剂受到阻碍。特别是，对考克斯-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。显然，需要鉴定具有更宽安全裕度的有效癌症预防剂。许多从食物中分离出来的癌症预防剂具有广泛的安全范围，如姜黄素，萝卜硫素和紫苏醇。理论上，可能不需要全身暴露于结肠直肠癌预防剂，因为口服给药的化合物将在所需的作用部位达到其最高浓度，即，胃肠道的内腔。因此，由于全身毒性与全身循环中的血液水平密切相关，即，根据药物动力学或毒理学，理想的结肠直肠癌预防剂将在靶胃肠组织中达到高局部浓度，但表现出有限的全身暴露至无全身暴露。这种局部递送概念是观察到的姜黄素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，但基于母体化合物具有可忽略的口服生物利用度。鉴定具有姜黄素样性质的其他化合物将为结直肠癌预防方式提供替代或潜在的组合药物。一个潜在的候选者是法尼醇，一种在包括结直肠癌在内的几种癌症模型中观察到临床前化学预防活性的类异戊二烯植物化学物质。特别是，法尼醇在Fisher F344大鼠的氧化偶氮甲烷异常隐窝病灶（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，这是由两个独立的研究小组完成的，其中一个研究小组由该基金的两位顾问共同撰写。此外，我们实验室的初步药代动力学研究表明，Sprague-Dawley大鼠经口给予14 C-法尼醇后，法尼醇被迅速和广泛代谢，表明全身生物利用度可忽略不计。因此，本提案的目的是进一步描述法尼醇的药代动力学，表征化合物的胃肠道组织处置，并确定Fisher F344大鼠（AOM：ACF研究中使用的品系）法尼醇的肠道渗透性和代谢。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。为了检验这一假设并追求项目目标，我们建议追求以下具体目标：SA 1：确定Fisher F344大鼠急性给药后和给药28天后法尼醇的药代动力学、口服生物利用度和基因表达效应。SA 2：测定法呢醇在Fisher F344大鼠中的肠道分布和肠道组织动力学。

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.