Probe Drugs for Botanical-Drug Interactions

描述（由申请人提供）：圣约翰草（SJW）是一种广泛使用的抗抑郁药。SJW的抗抑郁特性及其与其他药物的相互作用都与其金丝桃素含量有关，而不是金丝桃素。贯叶连翘素激活孕烷X受体（PXR），从而诱导药物代谢酶细胞色素P450（CYP）和转运蛋白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，焦点一直是基于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增强作用在个体之间差异超过40倍。我们最终打算探索CYP和核受体（PXR，CAR [组成型雄烷受体]等）的遗传差异（单核苷酸多态性，SNP）。发展基因型/表型关系的个体反应诱导剂。探针是用于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，安全和方便的探针酶代谢和运输最临床使用的药物：咖啡因（CYP 1A 2），氯沙坦（CYP 2C 9），美沙芬（CYP 2D 6？除了皮质醇（一种内源性CYPS A底物）外，还检测CYP 3A 4）、丁螺环酮（CYP 3A 4）和非索非那定（P-gp）。最初，我们建议评估将奥美拉唑加入CYP 2C 19和CYP 3A 4探针的可行性。（需要多个GYP 3A 4基板。）然后，我们将确定探针药物鸡尾酒的能力，以响应酶抑制和诱导SJW，使用产品标准化其贯叶金丝桃素含量。还将进行药物代谢酶和核受体的初始基因分型。最后，我们将确定鸡尾酒中的药物是否对酮康唑的代谢抑制敏感。拟议的研究将验证这种耐受性良好的探针鸡尾酒，用于研究SJW等草药诱导酶的基因组学。开发这样的工具是NIH路线图的一个目标。我们计划将来使用这些探针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：无处方销售的圣约翰草影响人们对许多处方药的反应。此外，并非所有人都受到同样程度的影响。这个项目将测试一个程序，以更好地了解和预测圣约翰草对处方药的影响。

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.