Modulation of drug metabolism by Danshen

说明(申请人提供)：许多临床使用的药物含有酯化学型，这是一种经常添加到小分子中以改善其水溶性和生物利用度的部分。然而，这些化合物中包含的这一功能使它们成为羧酸酯酶(CES)的底物，羧酸酯酶是一种可以灭活或激活这些试剂的酶。典型的例子包括抗癌剂CPT-11(伊立替康，Camptosar)，它是SN-38的前药，是一种有效的拓扑异构酶I毒物，以及抗病毒药物磷酸奥司他韦(达菲)，它需要水解到羧酸盐形式以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存在于中草药丹参中的化合物(丹参酮)。这种物质的提取物在体外可以有效地抑制人的CES并调节药物活性。然而，重要的是，FDA刚刚批准丹参在临床试验中的使用。因此，任何与中草药一起服用的酯化药物都可能导致分子水解率降低，从而降低该药剂的疗效。因此，我们试图评估丹参中的活性成分(S)，并评估这些分子是否可以在特定的动物模型中调节药物活性。这一应用的具体目的是：1)确定丹参中存在的抑制化合物；2)评估这些化合物抑制酶的机制；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/提取物对动物模型药物疗效的影响。我们预计，丹参中存在的化合物将抑制体内的CES，导致显著减少药物的水解度，从而降低药物疗效。由于这种材料目前处于临床试验中，从这些研究中获得的信息可能会确定新的药物：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。我们预计，这里提出的研究将验证这一假设，并提供关于在确定的患者群体中使用此类提取物的信息。

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.