Breath Test to Rapidly Evaluate 2D6 Enzyme Activity

Physical Sciences, Inc, Andover MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] One important consequence of inter-individual variability in drug disposition and response is the risk of adverse drug reactions. In the case of pharmacogenetic variability, genotypic and phenotypic characterization of individual patients or patient populations is of interest in an attempt to predict enzyme activity and potentially optimize drug safety and efficacy. Cytochrome P450 2D6 (CYP2D6) is a clinically important pathway that has been the subject of intense investigation by virtue of its role in the biotransformation of several commonly administered drugs. The goal of the proposed research is to develop a simple, rapid, noninvasive breath test for CYP2D6 activity based on the ingestion of (O-methyl-13C)-dextromethorphan hydrobromide, a stable isotope labeled (non-radioactive) version of the well-characterized CYP2D6 phenotyping probe, dextromethorphan hydrobromide, and measurement of the 13C02/1[unreadable]C02 ratio in expired breath using commercially available instrumentation. [unreadable] [unreadable] The Phase I program has three Specific Aims: [unreadable] [unreadable] 1. Produce the labeled CYP2D6 substrate (O-methyl-13C)-dextromethorphan hydrobromide (DM) according to 2003 United States Pharmacopeia standards. [unreadable] [unreadable] 2. Demonstrate (O-methyl-13C)-DM as a phenotyping probe for CYP2D6 activity in vivo. [unreadable] [unreadable] 3. Characterize the population distribution of CYP2D6 phenotypes using the breath test. [unreadable] [unreadable] The proposed program is a collaborative effort between Physical Sciences Inc., Cambridge Isotope Laboratories, and J. Steven Leeder, Pharm.D., Ph.D in the Section of Developmental Pharmacology and Therapeutics, Children's Mercy Hospital and Clinics, Kansas City MO. [unreadable] [unreadable] [unreadable]