Modulation of drug metabolism by Danshen

丹参对药物代谢的调节

• 批准号: 9127135
• 负责人: PHILIP M POTTER
• 金额: $ 43.75万
• 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 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127135
• 关键词: Animal Model; Antineoplastic Agents; Antiviral Agents; Biochemical; Biodistribution; Biological; Biological Availability; Camptothecin-11; Canis familiaris; Chinese Herbs; Chinese Traditional Medicine; Clinical Research; Clinical Trials; Drug Interactions; Drug Kinetics; Drug usage; Effectiveness; Enzyme Inhibition; Enzymes; Esters; Goals; Health; Herbal Medicine; Human; Hydrolysis; In Vitro; Individual; Kinetics; Lead; Metabolism; Neuraminidase inhibitor; Oseltamivir; Pharmaceutical Preparations; Pharmacotherapy; Plant Roots; Poison; Prodrugs; Protein Isoforms; Reaction; Rodent Model; SN-38; Salvia miltiorrhiza; Staging; Type I DNA Topoisomerases; biophysical techniques; 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 therapeutics; patient population; research study; response; small molecule; water solubility

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：许多临床使用的药物含有酯化学型，经常添加到小分子中以提高其水溶性和生物利用度。然而，在这些化合物中包含这种功能使它们成为羧酸酯酶（CEs）的底物，这些酶可以灭活或激活这些物质。典型的例子包括抗癌药物CPT-11（伊立替康，喜树碱），它是一种强效的拓扑异构酶I的前药，以及抗病毒药物磷酸奥司他韦（达菲），它需要水解成羧酸盐形式才能产生活性的神经氨酸酶抑制剂。因此，可能抑制水解反应的化合物将限制这些药物的功效。我们已经确定了一类化合物（丹参酮），存在于中药丹参中。该物质的提取物能有效抑制人ce并调节体外药物活性。然而，重要的是，FDA刚刚批准了丹参在临床试验中的使用。因此，任何酯化药物与草药联合施用都可能导致分子水解减少，从而减轻药物的功效。因此，我们寻求评估丹参中的活性成分，并评估这些分子是否可以在确定的动物模型中调节药物活性。本申请的具体目的是：1)测定丹参中存在的抑制化合物；2)评价这些化合物对酶的抑制作用机制；3)体外生物活性评价；4)确定这些化合物/提取物对动物模型药物功效的影响。我们预计丹参中的化合物会抑制体内ce，导致药物水解显著减少，从而降低药物功效。由于该材料目前处于临床试验阶段，从这些研究中获得的信息可能会识别出可能影响临床使用的酯化化合物有效性的新型药物：药物相互作用。我们设想这里提出的研究将验证这一假设，并提供有关在特定患者群体中使用此类提取物的信息。