Modulation of drug metabolism by Danshen

丹参对药物代谢的调节

• 批准号: 8625211
• 负责人: PHILIP M POTTER
• 金额: $ 41.56万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625211
• 关键词: Animal Model; Antineoplastic Agents; Antiviral Agents; Biochemical; Biodistribution; Biological; Biological Availability; Canis familiaris; Carboxylic Ester Hydrolases; Chinese Herbs; Clinical Research; Clinical Trials; Drug Interactions; Drug Kinetics; Drug usage; Effectiveness; Enzyme Inhibition; Enzymes; Esters; Goals; Herbal Medicine; Human; Hydrolysis; In Vitro; Individual; Kinetics; Lead; Medicine; Metabolism; Neuraminidase inhibitor; Oseltamivir; Pharmaceutical Preparations; Plant Roots; Poison; Prodrugs; Protein Isoforms; Reaction; Rodent Model; SN-38; Salvia miltiorrhiza; Staging; Techniques; Type I DNA Topoisomerases; carboxylate; carboxylesterase; cellular engineering; drug efficacy; drug metabolism; esterase; esterase inhibitor; improved; in vitro activity; in vivo; inhibitor/antagonist; inorganic phosphate; irinotecan; mouse model; novel; patient population; public health relevance; research study; response; small molecule; water solubility

Abstract Numerous clinically used agents contain the ester chemotype, a moiety frequently added to small molecules to improve their water solubility and bioavailability. However the inclusion of this function in these compounds makes them substrates for carboxylesterases (CEs), enzymes that can either inactivate or activate these agents. Typically examples include the anticancer agent CPT-11 (irinotecan, Camptosar) that is a prodrug of SN-38, a potent topoisomerase I poison, and the antiviral drug oseltamivir phosphate (Tamiflu) that requires hydrolysis to the carboxylate form to yield the active neuraminidase inhibitor. Hence, compounds that might inhibit the hydrolysis reactions would limit the efficacy of these drugs. We have identified a class of compounds (tanshinones) that are present within the Chinese herbal medicine Danshen. Extracts from this material can potently inhibit human CEs and modulate drug activity in vitro. Importantly however, the FDA has just approved the use of Danshen in clinical trials. Hence any esterified drug that is administered in conjunction with the herbal medicine might lead to reduced molecule hydrolysis, thereby mitigating the efficacy of the agent. We seek therefore, to evaluate the active component(s) in Danshen and to assess whether these molecules can modulate drug activity in defined animal models. The specific aims of this application are: 1) To determine the inhibitory compounds present within Danshen; 2) to assess the mechanism of enzyme inhibition by these compounds; 3) to assess the biological activity of these extracts in vitro; and 4) to determine the effect of such compounds/extracts on drug efficacy in animals models. We anticipate that compounds present within Danshen will inhibit the CEs in vivo, resulting in significantly reduced drug hydrolysis, and as a consequence, reduced drug efficacy. Since this material is currently in clinical trials, the information derived from these studies may identify novel drug:drug interactions that potentially would impact the effectiveness of clinically used esterified compounds. We envisage that the studies proposed here will validate this hypothesis and provide information concerning the use of such extracts in defined patient populations.

摘要 许多临床使用的药物都含有酯类化学型，这是一种经常添加到小分子 分子，以提高其水溶性和生物利用度。但是，将此函数包含在 这些化合物使它们成为羧酸酯酶(CES)的底物，这种酶可以 停用或激活这些代理。典型的例子包括抗癌剂CPT-11(伊立替康， Camptosar)，这是SN-38的前药，SN-38是一种有效的拓扑异构酶I毒药，以及抗病毒药物 磷酸奥司他韦(达菲)，需要水解成羧酸盐形式才能产生活性 神经氨酸酶抑制剂。因此，可能抑制水解反应的化合物将限制 这些药物的疗效。我们已经确定了一类化合物(丹参酮)，它们存在于 中草药丹参。这种物质的提取物可以有效地抑制人的CES和 在体外调节药物活性。然而，重要的是，FDA刚刚批准丹参在 临床试验。因此，任何与草药一起服用的酯化药物都可能 导致分子水解度降低，从而降低了药剂的功效。因此，我们寻求， 评价丹参有效成分(S)及其分子对药物的调节作用 已定义的动物模型中的活动。 这项应用的具体目的是：1)确定存在于 丹参；2)评估这些化合物的酶抑制机制；3)评估 这些提取物的体外生物活性；以及4)确定这些化合物/提取物对 药物在动物模型中的疗效。 我们预计，丹参中存在的化合物将抑制体内的CES，导致 大大减少了药物的水解度，因此降低了药物的疗效。因为这种材料 目前正在进行临床试验，从这些研究中获得的信息可能会确定新药：药物 可能会影响临床上使用的酯化化合物的有效性的相互作用。我们 设想这里提出的研究将验证这一假设并提供关于以下方面的信息 在确定的患者群体中使用这种提取物。