Enhancing Studies of Pharmacodynamic Mechanisms via Measurements of Metabolic Flux: Fundamental Concepts and Guiding Principles for Using Stable Isotope Tracers.

Title

Enhancing Studies of Pharmacodynamic Mechanisms via Measurements of Metabolic Flux: Fundamental Concepts and Guiding Principles for Using Stable Isotope Tracers.

Creator

Daurio Natalie A; Wang Sheng-Ping; Chen Ying; Zhou Haihong; McLaren David G; Roddy Thomas P; Johns Douglas G; Milot Denise; Kasumov Takhar; Erion Mark D; Kelley David E; Previs Stephen F

Publisher

The Journal of pharmacology and experimental therapeutics

Date

2017
2017-10

Description

Drug discovery and development efforts are largely based around a common expectation, namely, that direct or indirect action on a cellular process (e.g., statin-mediated enzyme inhibition or insulin-stimulated receptor activation) will have a beneficial impact on physiologic homeostasis. To expand on this, one could argue that virtually all pharmacologic interventions attempt to influence the flow of "traffic" in a biochemical network, irrespective of disease or modality. Since stable isotope tracer kinetic methods provide a measure of traffic flow (i.e., metabolic flux), their inclusion in study designs can yield novel information regarding pathway biology; the application of such methods requires the integration of knowledge in physiology, analytical chemistry, and mathematical modeling. Herein, we review the fundamental concepts that surround the use of tracer kinetics, define basic terms, and outline guiding principles via theoretical and experimental problems. Specifically, one needs to 1) recognize the types of biochemical events that change isotopic enrichments, 2) appreciate the distinction between fractional turnover and flux rate, and 3) be aware of the subtle differences between tracer kinetics and pharmacokinetics. We hope investigators can use the framework presented here to develop applications that address their specific questions surrounding biochemical flux, and thereby gain insight into the pathophysiology of disease states, and examine pharmacodynamic mechanisms.

Subject

Animals; Drug Discovery/*methods; Humans; Isotope Labeling; Isotopes/chemistry; Metabolic Flux Analysis/*methods; Water/chemistry/metabolism

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

80–91

Issue

1

Volume

363

Citation

Daurio Natalie A; Wang Sheng-Ping; Chen Ying; Zhou Haihong; McLaren David G; Roddy Thomas P; Johns Douglas G; Milot Denise; Kasumov Takhar; Erion Mark D; Kelley David E; Previs Stephen F, “Enhancing Studies of Pharmacodynamic Mechanisms via Measurements of Metabolic Flux: Fundamental Concepts and Guiding Principles for Using Stable Isotope Tracers.,” NEOMED Bibliography Database, accessed January 20, 2021, https://neomed.omeka.net/items/show/4527.

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