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Grant Abstract

Grant Number: 1R21AT002907-01A1
Project Title: Probe Drugs for Botanical-Drug Interactions

Abstract: 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.

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