Modulation of drug metabolism by Danshen

丹参对药物代谢的调节

基本信息

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
项目类别：
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

项目摘要

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包含酯化学型，这是一个经常添加到小分子中以提高其水溶性和生物利用度的部分。但是，将此功能纳入这些化合物，使其成为羧酸酯酶（CES）的底物，可以使这些剂失活或激活这些酶的酶。通常，示例包括抗癌剂CPT-11（Irinotecan，Camptosar），该前药是SN-38的前药，有效的拓扑异构酶I毒药和抗病毒药物磷酸磷酸oseltamivir磷酸盐（Tamiflu），需要将水解为羧酸盐形成，以产生活跃的神经酶酶酶促进性神经酶。因此，可能抑制水解反应的化合物将限制这些药物的功效。我们已经确定了中草药中存在的一类化合物（Tanshinones）。该材料的提取物可以有效抑制人类CES并在体外调节药物活性。但是，重要的是，FDA刚刚批准在临床试验中使用Danshen。因此，与草药结合使用的任何酯化药物都可能导致分子水解减少，从而降低剂的功效。因此，我们寻求评估Danshen中的活性成分，并评估这些分子是否可以调节定义的动物模型中的药物活性。本应用的具体目的是：1）确定丹森内存在的抑制化合物； 2）评估这些化合物抑制酶的机制； 3）在体外评估这些提取物的生物学活性； 4）确定此类化合物/提取物对动物模型中药物疗效的影响。我们预计，丹森（Danshen）中存在的化合物将抑制体内CES，从而大大降低药物水解，并因此降低了药物疗效。由于该材料目前正在临床试验中，因此从这些研究中得出的信息可能会确定新型药物：药物相互作用可能会影响临床使用的酯化化合物的有效性。我们设想，此处提出的研究将验证这一假设，并提供有关在定义的患者人群中使用此类提取物的信息。