US 2013/0273533 A1 · MOLECULAR FLUX RATES THROUGH CRITICAL PATHWAYS MEASURED BY STABLE ISOTOPE LABELING IN VIVO, AS BIOMARKERS OF DRUG ACTION AND DISEASE ACTIVITY

Abstract

The methods described herein enable the evaluation of compounds on subjects to assess their therapeutic efficacy or toxic effects. The target of analysis is the underlying biochemical process or processes (i.e., metabolic process) thought to be involved in disease pathogenesis. Molecular flux rates within the one or more biochemical processes serve as biomarkers and are quantitated and compared with the molecular flux rates (i.e., biomarker) from control subjects (i.e., subjects not exposed to the compounds). Any change in the biomarker in the subject relative to the biomarker in the control subject provides the necessary information to evaluate therapeutic efficacy of an administered drug or a toxic effect and to develop the compound further if desired. In one aspect of the invention, stable isotope-labeled substrate molecules are administered to a subject and the label is incorporated into targeted molecules in a manner that reveals molecular flux rates through one or more metabolic pathways of interest. By this method, a comparison between subjects and control subjects reveals the effects of the chemical entity or entities on the biomarkers. This, in turn, allows for the identification of potential therapeutic uses or toxicities of the compound. Combinations of compounds can also be systematically evaluated for complementary, synergistic, or antagonistic actions on the metabolic pathways of interest, using the methods of the present invention as a strategy for identifying and confirming novel therapeutic or toxic combinations of compounds.

Claims36

Dependent claims

A method for evaluating an action of one or more compounds on a molecular flux rate through a critical pathway as an authentic biomarker of disease or of compound activity, said method comprising:

a) exposing a living system to said one or more compounds;
b) administering an isotope-labeled substrate to said living system for a period of time sufficient for said isotope-labeled substrate to enter into one or more metabolic pathways of interest and thereby enter into and label at least one targeted molecule of interest within said one or more metabolic pathways of interest in said living system;
c) obtaining one or more samples from said living system, wherein said one or more samples comprise at least one isotope-labeled targeted molecule of interest;
d) measuring the content, rate of incorporation and/or pattern or rate of change in content and/or pattern of isotope labeling of said at least one targeted molecule of interest;
e) calculating molecular flux rates in said one or more metabolic pathways of interest based on the content and/or pattern or rate of change of content and/or pattern of isotopic labeling in said at least one targeted molecule of interest;
f) measuring the molecular flux rates in said one or more metabolic pathways of interest according to steps b) through e) in at least one living system not exposed to said one or more compounds as provided by step a);
and
g) comparing said molecular flux rates in said one or more metabolic pathways of interest in said living system administered said one or more compounds to said molecular flux rates in said one or more metabolic pathways of interest in said living system not administered said one or more compounds to evaluate the action of said one or more compounds on said molecular flux rates.

5 more elements

A method for evaluating an action of one or more compounds on a molecular flux rate through a critical pathway as an authentic biomarker of toxicity, said method comprising:

a) exposing a living system to one or more compounds;
b) administering an isotope-labeled substrate to said living system for a period of time sufficient for said isotope-labeled substrate to enter into one or more metabolic pathways of interest and thereby enter into and label one or more targeted molecules of interest within said one or more metabolic pathways of interest in said living system wherein said one or more metabolic pathways of interest are related to one or more toxic effects;
c) obtaining one or more samples from said living system, wherein said one or more samples comprise one or more isotope-labeled targeted molecules of interest;
d) measuring the content, rate of incorporation and/or pattern or rate of change in content and/or pattern of isotope labeling of said targeted molecule or molecules of interest;
e) calculating molecular flux rates in said one or more metabolic pathways of interest based on the content and/or pattern or rate of change of content and/or pattern of isotopic labeling in said molecule or molecules of interest;
f) measuring the molecular flux rates in said one or more metabolic pathways of interest according to steps b) through e) in a living system or systems not administered said one or more compounds;
and
g) comparing said molecular flux rates in said one or more metabolic pathways of interest in said living system administered said one or more compounds to said molecular flux rates in said one or more metabolic pathways in said living system or systems not administered said one or more compounds to evaluate the action of the one or more compounds on said molecular flux rates.

5 more elements

Dependencies are inferred from the claim text.

Molecular flux rates through critical pathways measured by stable isotope labeling in vivo, as biomarkers of drug action and disease activity

Life of this patent

Molecular flux rates through critical pathways measured by stable isotope labeling in vivo, as biomarkers of drug action and disease activity

Life of this patent

Abstract

Claims36