Pharmacometabolomics: Implications for Clinical Pharmacology and Systems Pharmacology

Abstract

Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

“…We previously reported in the same population that aspirin decreased the levels of many of the most abundant FAs,15, 16, 17, 42 including oleic (−28%), palmitic (−10%), palmitoleic (−31%), mystiric (−15%), and lauric (−15%) acids, as well as glycerol levels (−13%) 5, 18, 19. The concomitant decrease of free fatty acids and glycerol indicates a potential inhibition of lipolysis by aspirin in our subjects.…”

“…Pharmacometabolomics is an emerging field that aims to use metabolomics tools to define the mechanisms of action for drugs and the biochemical basis for variation in response to treatment 18, 19. Metabolic profiles integrate genetic and environmental influences and provide unique information that can help explain the drug–response phenotype 20, 21.…”

Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes

“…Recently, several studies successfully used pharmacometabolomics to identify novel biomarkers and explain variation in drug response (e.g., sertraline, escitalopram, aspirin) 8, 9, 10, 11, 12, 13, 14. Furthermore, metabolic phenotypes have been used to explain variation in BP across ethnic groups 13.…”

Does Citrulline Sit at the Nexus of Metformin’s Pleotropic Effects on Metabolism and Mediate Its Salutatory Effects in Individuals With Type 2 Diabetes?

“…Clinically, metformin also reduces the risk for cardiovascular diseases, cancers, and other diseases (5,6). Pharmacometabolomics provides an opportunity to measure changes in absolute and/or relative concentrations of hundreds to thousands of small molecules in biofluids and tissue extracts to determine the response and variations in response to therapy (7). Pharmacometabolomics could facilitate identification of metabolic pathways and mechanisms of action that contribute to metformin's widespread salutatory effects (7).…”

“…Pharmacometabolomics provides an opportunity to measure changes in absolute and/or relative concentrations of hundreds to thousands of small molecules in biofluids and tissue extracts to determine the response and variations in response to therapy (7). Pharmacometabolomics could facilitate identification of metabolic pathways and mechanisms of action that contribute to metformin's widespread salutatory effects (7). In this issue of Diabetes, Adam et al (8) utilize this approach to "uncover" metformin's effect on citrulline metabolism in individuals with and without T2D participating in the KORA (Cooperative Health Research in the Region of Augsburg) study.…”