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Abstract
Grant Number: 1R43AI071657-01A2 Project Title: Pharmacogenetic Analysis of CYP450 SNP Enzymes
PI Information: Name Title KIM, RAYMOND rkim@geneprism.com Abstract: DESCRIPTION (provided by applicant): Genetic polymorphisms in genes encoding cytochrome P450s (CYP) have been shown to be determinants of inter-individual variability in drug response and drug disposition. These polymorphisms occur in human populations at variable rates, and predicting adverse drug reactions by genotyping of these polymorphisms has the potential to optimize drug choice and doses for more effective therapy, to avoid serious adverse effects, and to decrease medical costs. Currently, only a handful of CYP enzymes are used by pharmaceutical companies in their drug metabolism evaluations. The specific aim of this Phase 1 study is to develop and validate a comprehensive panel of polymorphic CYP enzymes with which to study the phenotypic effects of 104 non-synonymous polymorphisms occurring in 2C19, 2D6, and 3A4 subfamilies of CYP. These CYPs metabolize the bulk of prescription drugs, and the polymorphisms which cause loss or alterations in the catalytic property of the variant enzymes may likely have significant impact in the metabolic trajectory of drugs. In this project, the enzymes corresponding to these 104 polymorphisms will be expressed in recombinant form and will be characterized to generate Km, Vmax, intrinsic clearance, and Ki values to 40 prescription drugs. Since the majority of the selected polymorphisms have not been characterized at any level, the outcome of this project will produce functional information as to which polymorphisms produce active or inactive enzymes, which polymorphisms cause altered enzyme fitness, and which enzyme variants possess modified behaviors to drugs. The ultimate applications of this pharmacogenetic tool will be in routine screening of this panel of enzymes in pre-clinical and clinical stages of drug development to weed out compounds and drug candidates which could have harmful effect when paired with certain CYP polymorphisms. In addition, when applied together with multiplexed CYP genotyping devices, the pharmacogenetic information generated using this technology can be used to prognosticate incompatible pairing of drugs with genotypes to reduce potential adverse drug responses in patients. Human cytochrome P450 enzymes play a major role in drug metabolism. Numerous genetic variations (or single nucleotide polymorphisms) in cytochrome P450 enzymes have been identified in human populations, and many of them have been shown to be important determinants of adverse drug responses in patients. This Phase 1 SBIR application proposes to develop a panel of proteins corresponding to these genetic polymorphisms in order to study their functionality and phenotypes. This pharmacogenetic tool will provide important first step toward predicting adverse pairing of drugs with P450 polymorphisms for personalized medicine.
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Institution: GENEPRISM, INC. 10396 AMISTAD CRT CUPERTINO, CA 950142606 Fiscal Year: 2007 Department: Project Start: 15-SEP-2007 Project End: 29-FEB-2008 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1