Probe Drugs for Botanical-Drug Interactions

描述（申请人提供）：圣约翰草（SJW）是一种广泛使用的抗抑郁药。SJW的抗抑郁作用及其与其他药物的相互作用与金丝桃素含量有关，而与金丝桃素无关。hyperperin激活孕烷X受体（PXR），从而诱导药物代谢酶细胞色素p450 （CYPs）和转运体p -糖蛋白（P-gp）的活性。药物基因组学是一门快速发展的学科，其目标是根据个体的基因型定制药物治疗。到目前为止，重点是根据药物代谢酶的多态性来调整单一药物的剂量。由于患者经常同时服用多种药物，我们的长期目标是探索药物代动力学（PK）药物相互作用的基因组学。诱导剂对药物代谢的促进作用在个体之间的差异超过40倍。我们最终打算探索CYPs和核受体（PXR， CAR[组成型雄甾烷受体]等）的遗传差异（单核苷酸多态性，snp），以建立个体对诱导剂反应的基因型/表型关系。探针是用来研究药物处置的药物。我们已经开发了一种探针药物鸡尾酒，可以安全方便地检测代谢和运输大多数临床使用药物的酶：咖啡因（CYP1A2），氯沙坦（CYP2C9），右美沙芬(CYP2D6？还检测CYP3A4)、丁螺环酮（CYP3A4）和非索非那定（P-gp），以及内源性CYPS A底物皮质醇。我们初步拟评估加入奥美拉唑检测CYP2C19和CYP3A4的可行性。（需要多种GYP3A4衬底。）然后，我们将使用一种标准化的产品来确定探针药物鸡尾酒对SJW酶抑制和诱导的反应能力。药物代谢酶和核受体的初始基因分型也将进行。最后，我们将确定鸡尾酒中的药物是否容易被酮康唑抑制代谢。所提出的研究将验证这种耐受性良好的探针鸡尾酒，用于草药如SJW诱导酶的基因组学研究。开发这样的工具是NIH路线图的一个目标。我们计划未来使用这些探针来寻找人类基因组标记来预测药物相互作用。与公共卫生的相关性：圣约翰草无处方销售，影响人们对许多处方药的反应方式。此外，并非所有人都受到同样程度的影响。这个项目将测试一种程序，以更好地了解和预测圣约翰草对人类处方药的影响。

DESCRIPTION (provided by applicant): St. John's Wort (SJW) is a widely used antidepressant. Both the antidepressant properties of SJW and its interactions with other drugs are related to its hyperforin content, not to hypericin. Hyperforin activates the Pregnane X Receptor (PXR), thereby inducing activities of drug metabolizing enzymes, cytochrome P450s (CYPs), and the transporter, P-glycoprotein (P-gp). Pharmacogenomics is a rapidly developing discipline whose objective is to customize drug therapy based on an individual's genotype. Thus far, the focus has been on adjusting doses of single drugs based on polymorphisms of drug metabolizing enzymes. As patients often take many drugs at once, our long term goal is to explore the genomics of pharmacokinetic (PK) drug interactions. Enhancement of drug metabolism by inducers varies by over 40 fold among individuals. We ultimately intend to explore genetic differences (Single Nucleotide Polymorphisms, SNPs) in CYPs and nuclear receptors (PXR, CAR [Constitutive Androstane Receptor], etc.) to develop genotype/phenotype relationships for individual responses to inducers. Probes are drugs used to study drug disposition. We have developed a probe drug cocktail that safely and conveniently probes for enzymes that metabolize and transport most clinically used drugs: caffeine (CYP1A2), losartan (CYP2C9), dextromethorphan (CYP2D6?also probes for CYP3A4), buspirone (CYP3A4), and fexofenadine (P-gp), in addition to cortisol, an endogenous CYPS A substrate. Initially, we propose to evaluate the feasibility of adding omeprazole to probe for CYP2C19 and for CYP3A4. (Multiple GYP3A4 substrates are desirable.) Then we will determine the ability of the probe drug cocktail to respond to enzyme inhibition and induction by SJW, using a product standardized to its hyperforin content. Initial genotyping of drug metabolizing enzymes and nuclear receptors will also be performed. Finally, we will determine if the drugs in the cocktail are susceptible to inhibition of metabolism by ketoconazole. The proposed studies will validate this well-tolerated probe cocktail for research into genomics of induction of enzymes by herbs like SJW. Development of such tools is a goal of the NIH Roadmap. We plan future use of these probes to look for human genomic markers to predict drug interactions. Relevance to public health: Saint John's wort, sold without prescription, affects the way that people respond to many prescription drugs. In addition, not all people are affected to the same extent. This project wjll test a procedure to better understand and predict the effects of Saint John's wort on prescription drugs in people.