Pharmacometabolomics, also known as pharmacometabonomics, is a field which stems from

metabolomics Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprin ...

, the quantification and analysis of

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

produced by the body. It refers to the direct measurement of

in an individual's bodily fluids, in order to predict or evaluate the

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

compounds, and to better understand the pharmacokinetic profile of a drug. Alternatively, pharmacometabolomics can be applied to measure

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

levels following the administration of a

compound, in order to monitor the effects of the compound on certain metabolic pathways(pharmacodynamics). This provides detailed mapping of drug effects on metabolism and the pathways that are implicated in mechanism of variation of response to treatment. In addition, the metabolic profile of an individual at baseline (metabotype) provides information about how individuals respond to treatment and highlights heterogeneity within a disease state. All three approaches require the quantification of

found in

bodily fluids Body fluids, bodily fluids, or biofluids, sometimes body liquids, are liquids within the human body. In lean healthy adult men, the total body water is about 60% (60–67%) of the total body weight; it is usually slightly lower in women (52-55%) ...

and tissue, such as blood or urine, and can be used in the assessment of

treatment options for numerous

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

states.

Goals of Pharmacometabolomics

Pharmacometabolomics is thought to provide information that complements that gained from other

omics The branches of science known informally as omics are various disciplines in biology whose names end in the suffix '' -omics'', such as genomics, proteomics, metabolomics, metagenomics, phenomics and transcriptomics. Omics aims at the collect ...

, namely

genomics Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...

transcriptomics Transcriptomics technologies are the techniques used to study an organism's transcriptome, the sum of all of its RNA transcripts. The information content of an organism is recorded in the DNA of its genome and expressed through transcription. He ...

, and

proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...

. Looking at the characteristics of an individual down through these different levels of detail, there is an increasingly more accurate prediction of a person's ability to respond to a

compound. The

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

, made up of 25 000

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, can indicate possible errors in drug

; the

transcriptome The transcriptome is the set of all RNA transcripts, including coding and non-coding, in an individual or a population of cells. The term can also sometimes be used to refer to all RNAs, or just mRNA, depending on the particular experiment. The t ...

, made up of 85,000 transcripts, can provide information about which genes important in

are being actively transcribed; and the

proteome The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. ...

, >10,000,000 members, depicts which

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

are active in the body to carry out these functions. Pharmacometabolomics complements the

with direct measurement of the products of all of these reactions, but with perhaps a relatively smaller number of members: that was initially projected to be approximately 2200

, but could be a larger number when gut derived metabolites and xenobiotics are added to the list. Overall, the goal of pharmacometabolomics is to more closely predict or assess the response of an individual to a

compound, permitting continued treatment with the right drug or dosage depending on the variations in their

and ability to respond to treatment. Pharmacometabolomic analyses, through the use of a

approach, can provide a comprehensive and detailed metabolic profile or “ metabolic fingerprint” for an individual patient. Such metabolic profiles can provide a complete overview of individual

or pathway alterations, providing a more realistic depiction of

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

. This approach can then be applied to the prediction of response to a

compound by patients with a particular metabolic profile. Pharmacometabolomic analyses of drug response are often coupled or followed up with

pharmacogenetics Pharmacogenomics is the study of the role of the genome in drug response. Its name ('' pharmaco-'' + ''genomics'') reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects the ...

studies.

Pharmacogenetics Pharmacogenomics is the study of the role of the genome in drug response. Its name ('' pharmaco-'' + ''genomics'') reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects the ...

focuses on the identification of genetic variations (e.g.

single-nucleotide polymorphisms In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

) within patients that may contribute to altered drug responses and overall outcome of a certain treatment. The results of pharmacometabolomics analyses can act to “inform” or “direct” pharmacogenetic analyses by correlating aberrant

concentrations or metabolic pathways to potential alterations at the genetic level. This concept has been established with two seminal publications from studies of antidepressants serotonin reuptake inhibitors where metabolic signatures were able to define pathway implicated in response to the antidepressant and that lead to identification of genetic variants within a key gene within highlighted pathway as being implicated in variation in response. These genetic variants were not identified through genetic analysis alone and hence illustrated how metabolomics can guide and inform genetic data.

History

Although the applications of pharmacometabolomics to

personalized medicine Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on the ...

are largely only being realized now, the study of an individual's

has been used to treat disease since the Middle Ages. Early physicians employed a primitive form of metabolomic analysis by smelling, tasting and looking at urine to diagnose disease. Obviously the measurement techniques needed to look at specific

were unavailable at that time, but such technologies have evolved dramatically over the last decade to develop precise, high-throughput devices, as well as the accompanying data analysis software to analyze output. Currently, sample purification processes, such as

liquid A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, a ...

gas chromatography Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, ...

, are coupled with either mass spectrometry (MS)-based or nuclear magnetic resonance (NMR)-based analytical methods to characterize the

profiles of individual patients. Continually advancing

informatics Informatics is the study of computational systems, especially those for data storage and retrieval. According to ACM ''Europe and'' ''Informatics Europe'', informatics is synonymous with computer science and computing as a profession, in which ...

tools allow for the identification, quantification and classification of

to determine which pathways may influence certain

interventions. One of the earliest studies discussing the principle and applications of pharmacometabolomics was conducted in an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

to look at the

paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...

and liver damage.

NMR spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fiel ...

was used to analyze the urinary metabolic profiles of rats pre- and post-treatment with

. The analysis revealed a certain metabolic profile associated with increased liver damage following

treatment. At this point, it was eagerly anticipated that such pharmacometabolomics approaches could be applied to

personalized Personalization (broadly known as customization) consists of tailoring a service or a product to accommodate specific individuals, sometimes tied to groups or segments of individuals. A wide variety of organizations use personalization to improv ...

human

medicine Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...

. Since this

publication To publish is to make content available to the general public.Berne Conve ...

in 2006, the Pharmacometabolomics Research Network led by Duke University researchers and that included partnerships between centers of excellence in metabolomics, pharmacogenomics and informatics (over sixteen academic centers funded by NIGMS) has been able to illustrate for the first time the power of the pharmacometabolomics approach in informing about treatment outcomes in large clinical studies and with use of drugs that include antidepressants, statins, antihypertensives, antiplatelet therapies and antipsychotics. Totally new concepts emerged from these studies on use of pharmacometabolomics as a tool that can bring a paradigm shift in the field of pharmacology. It illustrated how pharmacometabolomics can enable a Quantitative and Systems Pharmacology approach. Pharmacometabolomics has been applied for the treatment of numerous human diseases, such as

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

, neural disease, depression and

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

Personalized Medicine

analyses are being conducted at the individual patient level, pharmacometabolomics may be considered a form of

. This field is currently being employed in a predictive manner to determine the potential responses of therapeutic compounds in individual patients, allowing for more customized treatment regimens. It is anticipated that such pharmacometabolomics approaches will lead to the improved ability to predict an individual's response to a compound, the efficacy and metabolism of it as well as adverse or off-target effects that may take place in the body. The metabolism of certain drugs varies from patient to patient as the

copy number Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...

of the

which code for common drug metabolizing

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

varies within the population, and leads to differences in the ability of an individual to metabolize different compounds. Other important personal factors contributing to an individual's metabolic profile, such as patient nutritional status, commensal

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

, age, and pre-existing medical conditions, are also reflected in

assessment., Overall, pharmacometabolomic analyses combined with such approaches as

, can function to identify the

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

processes and particular

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

tic alterations that may compromise the anticipated efficacy of a drug in a particular patient. The results of such analyses can then allow modification of treatment regimens for an optimal outcome.

Current Applications

Predicting treatment outcome

Metabotype informs about treatment outcomes

Pharmacometabolomics may be used in a predictive manner to determine the correct course of action in regards to a patient about to undergo some type of drug treatment. This involves determining the metabolic profile of a patient prior to treatment, and correlating metabolic signatures with the outcome of a

treatment course. Analysis of a patient's metabolic profile can reveal factors that may contribute to altered drug

, allowing for predictions of the overall efficacy of a proposed treatment, as well as potential

drug toxicity An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...

risks that may differ from the general population. This approach has been used to identify novel or previously characterized metabolic

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

in patients, which can be used to predict the expected outcome of that patient following treatment with a pharmaceutical compound. One example of the clinical application of pharmacometabolomics are studies that looked to identify a predictive metabolic marker for the treatment of major depressive disorder (MDD)., In a study with antidepressant Sertraline, the Pharmacometabolomics Network illustrated that metabolic profile at baseline of patients with major depression can inform about treatment outcomes. In addition the study illustrated the power of metabolomics for defining response to placebo and compared response to placebo to response to sertraline and showed that several pathways were common to both. In another study with escitalopram citalopram, metabolomic analysis of

plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...

from patients with MDD revealed that variations in

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

metabolism were negatively associated with patient outcome upon treatment with selective serotonin reuptake inhibitors (SSRIs), an important drug class involved in the treatment of this disease.

Monitoring drug-related alterations in metabolic pathways

The second major application of pharmacometabolomics is the analysis of a patient's metabolic profile following the administration of a specific therapy. This process is often secondary to a pre-treatment metabolic analysis, allowing for the comparison of pre- and post-treatment

concentrations. This allows for the identification of the metabolic processes and pathways that are being altered by the treatment either intentionally as a designated

target Target may refer to: Physical items * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artillery, fi ...

of the compound, or unintentionally as a

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. Furthermore, the concentration and variety of

produced from the compound itself can also be identified, providing information on the rate of

and potentially leading to development of a related compound with increased efficacy or decreased

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. An example of this approach was used to investigate the effect of several

antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

drugs on

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...

in patients treated for

. It was hypothesized that these

drugs may be altering

in treated patients with

, contributing to the weight gain and

hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and h ...

. The study monitored

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

metabolites in patients both before and after treatment with

antipsychotics Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...

. The compiled pre- and post-treatment profiles were then be compared to examine the effect of these compounds on

. The researchers found correlations between treatment with

drugs and

, in both a lipid-class-specific and drug-specific manner, establishing new foundations around the concept that pharmacometabolomics provides powerful tools for enabling detailed mapping of drug effects. Additional studies by the Pharmacometabolomics Research Network enabled mapping in ways not possible before effects of statins, atenolol and aspirin. Totally new insights were gained about effect of these drugs on metabolism and they highlighted pathways implicated in response and side effects.

Metabolite Quantification and Analysis

In order to identify and quantify metabolites produced by the body, various detection methods have been employed. Most often, these involve the use of

nuclear magnetic resonance (NMR) spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a Spectroscopy, spectroscopic technique to observe local magnetic fields around Atomic nucleus, atomic nuclei. The sampl ...

or mass spectrometry (MS), providing universal detection, identification and quantification of metabolites in individual patient samples. Although both processes are used in pharmacometabolomic analyses, there are advantages and disadvantages for using either

- or mass spectrometry (MS)-based platforms in this application.

Nuclear Magnetic Resonance Spectroscopy

has been utilized for the analysis of biological samples since the 1980s, and can be used as an effective technique for the identification and quantification of both known and unknown metabolites. For details on the principles of this technique, see

. In pharmacometabolomics analyses,

NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...

is advantageous because minimal sample preparation is required. Isolated patient samples typically include blood or urine due to their minimally-invasive acquisition, however, other fluid types and solid tissue samples have also been studied with this approach. Due to the minimal preparation of samples before analysis, samples can be potentially fully recovered following

analysis (If samples are kept refrigerated to avoid degradation). This permits samples to be repeatedly analysed with extremely high levels of reproducibility, as well as maintaining precious patient samples for an alternative analysis. The high reproducibility and precision of

, coupled with relatively fast processing time (greater than 100 samples per day), makes this process a relatively high-throughput form of sample analysis. One disadvantage of this technique is the relatively poor metabolite detection sensitivity compared to MS-based analysis, leading to a requirement for greater initial sample volume. Furthermore, the initial instrument costs are extremely high, for both

and MS equipment.

Mass Spectrometry

An alternative approach to the identification and quantification of patient samples is through the use of mass spectrometry. This approach offers excellent precision and sensitivity in the identification, characterization and quantification of metabolites in multiple patient sample types, such as blood and urine. The mass spectrometry (MS) approach is typically coupled to gas chromatography (GC), in GC-MS or liquid chromatography (LC), in LC-MS, which aid in initially separating out the metabolite components within complex sample mixtures, and can allow for the isolation of particular metabolite subsets for analysis. GC-MS can provide relatively precise quantification of metabolites, as well as chemical structural information that can be compared to pre-existing chemical libraries. GC-MS can be conducted in a relatively high-throughput manner (greater than 100 samples per day) with greater detection sensitivity than

analysis. A limitation of GC-MS for this application, however, is that processed metabolite components must be readily volatilized for sample processing. LC-MS initially separates out the components of a sample mixture based on properties such as hydrophobicity, before processing them for identification and quantification by mass spectrometry (MS). Overall, LC-MS is an extremely flexible method for processing most compound types in a somewhat high-throughput manner (20-100 samples a day), also with greater sensitivity than

analysis. For both GC-MS and LC-MS there are limitations in the reproducibility of metabolite quantification. Furthermore, sample processing for downstream mass spectrometry (MS) analysis is much more intensive than in

application, and results in the destruction of the original sample (via

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...

digestion). Following identification and quantification of metabolites in individual patient samples,

and mass spectrometry (MS) output is compiled into a dataset. These datasets include information on the identity and levels of individual metabolites detected within processed samples, as well as characteristics of each metabolite during the detection process (e.g. mass-to-charge ratios for mass spectrometry (MS)-based analysis). Multiple datasets can be created and compiled into large databases for individual patients in order to monitor varying metabolic profiles over a treatment course (i.e. pre- and post-treatment profiles). Each database is then processed through a type of informatics platform with software designed to characterize and analyze the data to generate an overall metabolic profile for the patient. To generate this overall profile, computational programs are designed to: * identify metabolic disease signatures * assess treatment class (pre- or post-treatment) * identify compounds present in a patient sample that may alter drug response, or be caused by a therapy * identify metabolite variables and interactions among these variables * map identified variables to known metabolic and biochemical pathways

Limitations

Along with the emerging diagnostic capabilities of pharmacometabolomics, there are limitations introduced when individual variability is looked at. The ability to determine an individual's physiological state by measurement of metabolites is not contested, but the extreme variability that can be introduced by age, nutrition, and commensal organisms suggest problems in creating generalized pharmacometabolomes for patient groups. However, as long as meaningful metabolic signatures can be elucidated to create baseline values, there still exists a possible means of comparison. Issues surrounding the measurement of metabolites in an individual can also arise from the methodology of metabolite detection, and there are arguments both for and against

and mass spectrometry (MS). Other limitations surrounding metabolite analysis include the need for proper handling and processing of samples, as well as proper maintenance and calibration of the analytical and computational equipment. These tasks require skilled and experienced technicians, and potential instrument repair costs due to continuous sample processing can be costly. The cost of the processing and analytical platforms alone is very high, making it difficult for many facilities to afford pharmacometabolomics-based treatment analyses.

Implications for Health Care

Pharmacometabolomics may decrease the burden on the healthcare system by better gauging the correct choice of treatment drug and dosage in order to optimize the response of a patient to a treatment. Hopefully, this approach will also ultimately limit the number of adverse drug reactions (ADRs) associated with many treatment regimens. Overall, physicians would be better able to apply more personalized, and potentially more effective, treatments to their patients. It is important to consider, however, that the processing and analysis of the patient samples takes time, resulting in delayed treatment. Another concern about the application of pharmacometabolomics analyses to individual patient care, is deciding who should and who should not receive this in-depth, personalized treatment protocol. Certain diseases and stages of disease would have to be classified according to their requirement of such a treatment plan, but there are no criteria for this classification. Furthermore, not all hospitals and treatment institutes can afford the equipment to process and analyze patient samples on site, but sending out samples takes time and ultimately delays treatment. Health insurance coverage of such procedures may also be an issue. Certain insurance companies may discriminate against the application of this type of sample analysis and metabolite characterization. Furthermore, there would have to be regulations put in place to ensure that there was no discrimination by insurance companies against the metabolic profiles of individual patients (“high metabolizers” vs. risky “low metabolizers”).

References

{{reflist, refs= {{cite journal, last=Kaddurah-Daouk, first=R , author2=Kristal, B , author3=Weinshilboum, RM, title=Metabolomics: A Global Biochemical Approach to Drug Response and Disease, journal=Annual Review of Pharmacology and Toxicology, year=2008, volume=48, pages=653–683, doi=10.1146/annurev.pharmtox.48.113006.094715, pmid=18184107 {{cite journal, last=Kaddurah-Daouk, first=R, author2=Weinshilboum, RM, title=Pharmacometabolomics: Implications for Clinical Pharmacology and Systems Pharmacology, journal=Clinical Pharmacology and Therapeutics, year=2014, volume=95, issue=2, pages=154–167, doi=10.1038/clpt.2013.217, pmid=24193171, s2cid=22649568 {{cite journal, last1=Kaddurah-Daouk, first1=R, last2=Yuan, first2=P, last3=Boyle, first3=SH, last4=Matson, first4=W, last5=Wang, first5=Z, last6=Zeng, first6=Z, last7=Zhu, first7=H, last8=Dougherty, first8=GG, last9=Yao, first9=JK, last10=Chen, first10=G, last11=Guitart, first11=X, last12=Carlson, first12=PJ, last13=Neumeister, first13=A, last14=Zarate, first14=C, last15=Krishnan, first15=RR, last16=Manji, first16=HK, last17=Drevets, first17=W, title=Cerebrospinal Fluid Metabolome in Mood Disorders., journal=Scientific Reports, year=2012, volume=2, pages=667, doi=10.1038/srep00667, pmc=3446657, pmid=22993692 {{cite journal, last=Kaddurah-Daouk, first=R , author2=Baillie RA , author3=Zhu H , author4=Zeng ZB , author5=Wiest MM , author6=Nguyen UT , author7=Watkins SM , author8=Krauss RM, title=Lipidomics analysis of variation in response to simvastatin in the cholesterol and pharmacogenetics study., journal=Metabolomics, year=2010, volume=6, issue=2 , pages=191–201, doi=10.1007/s11306-010-0207-x, pmid=20445760 , pmc=2862962 , doi-access=free {{cite journal, last=Kaddurah-Daouk, first=R , author2=Baillie RA , author3=Zhu H , author4=Zeng ZB , author5=Wiest MM , author6=Nguyen UT , author7=Wojnoonski K , author8=Watkins SM , author9=Trupp M , author10=Krauss RM, title=Enteric Microbiome correlates with response to simvastatin treatment., journal=PLOS ONE, year=2011, volume=6, issue=10, doi=10.1371/journal.pone.0025482, pages=e25482 , pmid=22022402 , pmc=3192752, doi-access=free {{cite journal, last=Trupp, first=M , author2=Zhu H , author3=Wikoff WR , author4=Baillie RA , author5=Zeng ZB , author6=Karp PD , author7=Fiehn O , author8=Krauss RM , author9=Kaddurah-Daouk R, title=Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment., journal=PLOS ONE, year=2012, volume=7, issue=7, doi=10.1371/journal.pone.0038386, pages=e38386 , pmid=22808006 , pmc=3392268, doi-access=free {{cite journal, last=Kaddurah-Daouk, first=R , author2=Boyle SH , author3=Matson W , author4=Sharma S , author5=Matson S , author6=Zhu H , author7=Bogdanov MB , author8=Churchill E , author9=Krishnan RR , author10=Rush AJ , author11=Pickering E , author12=Delnomdedieu M, title=Pretreatment Metabotype as a Predictor of Response to Sertraline or Placebo in Depressed Outpatients: A Proof of Concept., journal=Translational Psychiatry, year=2011, volume=1, issue=7, doi=10.1038/tp.2011.22, pages=e26, pmid=22162828 , pmc=3232004 , doi-access=free {{cite journal, last=Weiss, first=RH, author2=Kim, K, title=Metabolomics in the study of kidney disease, journal=Nature Reviews Nephrology, year=2012, volume=8, pages=22–33, doi=10.1038/nrneph.2011.152, pmid=22025087, issue=1, s2cid=23576016 {{cite journal, last=Baraldi, first=E , author2=Carraro, S , author3=Giordano, G , author4=Reniero, F , author5=Perilongo, G , author6=Zacchello, F, title=Metabolomics: moving towards personalized medicine, journal=Italian Journal of Pediatrics, year=2009, volume=35, issue=30, page=30 , doi=10.1186/1824-7288-35-30, pmid=19852788, pmc=2773773 {{cite journal, last=Abo, first=R , author2=Hebbring, S , author3=Ji, Yuan, title=Merging pharmacometabolomics with pharmacogenomics using '1000 Genomes' single-nucleotide polymorphism imputation: selective serotonin reuptake inhibitor response pharmacogenomics., journal=Pharmacogenetics and Genomics, year=2012, doi=10.1097/FPC.0b013e32835001c9, pmid=22322242, volume=22, issue=4, pages=247–53, display-authors=etal, pmc=3303952 {{cite journal, last1=Ji, first1=Y, last2=Hebbring, first2=S, last3=Zhu, first3=H, last4=Jenkins, first4=GD, last5=Biernacka, first5=J, last6=Snyder, first6=K, last7=Drews, first7=M, last8=Fiehn, first8=O, last9=Zeng, first9=Z, last10=Schaid, first10=D, last11=Mrazek, first11=DA, last12=Kaddurah-Daouk, first12=R, last13=Weinshilboum, first13=RM, title=Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics, journal=Clinical Pharmacology and Therapeutics, year=2011, volume=89, issue=1, pages=97–104, doi=10.1038/clpt.2010.250, pmc=3034442, pmid=21107318 {{cite journal, last=Clayton, first=A , author2=Lindon, JC , author3=Cloarec, O, title=Pharmaco-metabonomic phenotyping and personalized drug treatment, journal=Nature , year=2006, volume=440, pages=1073–1077, doi=10.1038/nature04648, pmid=16625200, issue=7087, s2cid=4424842 , url=http://gala.gre.ac.uk/id/eprint/4415/1/Nature_Pharmacometabonomics_2006.docx , display-authors=etal {{cite journal, last=Motulsky, first=AG, title=Drug reactions enzymes, and biochemical genetics, journal=Journal of the American Medical Association, year=1957, volume=165, pages=835–837, pmid=13462859, issue=7, doi=10.1001/jama.1957.72980250010016 {{cite journal, last=Corona, first=G , author2=Rizzolio, F , author3=Giodano, A , author4=Toffoli, G, title=Pharmaco-metabolomics: an emerging "omics" tool for the personalization of anticancer treatments and identification of new valuable therapeutic targets., journal=Journal of Cellular Physiology, year=2011, doi=10.1002/jcp.24003, pmid=22105661, volume=227, issue=7, pages=2827–31, s2cid=26060357 {{cite journal, last=Zhu, first=H , author2=Bogdanov MB , author3=Boyle SH , author4=Matson W , author5=Sharma S , author6=Matson S , author7=Churchill E , author8=Fiehn O , author9=Rush JA , author10=Krishnan RR , author11=Pickering E , author12=Delnomdedieu M , author13=Kaddurah-Daouk R , author14=Network PR, title=Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway., journal=PLOS ONE, year=2013, volume=8, issue=7, doi= 10.1371/journal.pone.0068283, pages=e68283 , pmid=23874572 , pmc=3714282, doi-access=free {{cite journal, last=Kaddurah-Daouk, first=R , author2=McEvoy, J , author3=Baillie, RA, title=Metabolomic mapping of atypical antipsychotic effects in schizophrenia, journal=Molecular Psychiatry, year=2007, doi=10.1038/sj.mp.4002000, pmid=17440431, volume=12, issue=10, pages=934–45, display-authors=etal, doi-access=free {{cite journal, last=Krauss, first=R , author2=Zhu H , author3=Kaddurah-Daouk R, title=Pharmacometabolomics of statin Response, journal=Clinical Pharmacology and Therapeutics, year=2013, volume=94, issue=5, pages=562–5, doi=10.1038/clpt.2013.164, pmc=4055080, pmid=23945822 {{cite journal, last=Wikoff, first=WR , author2=Frye, RF , author3=Zhu, H , author4=Boyle, S , author5=Churchill, E , author6=Gong, Y , author7=Cooper-Deho, RM , author8=Beitelshees, AL , author9=Lane, A , author10=Chapman, AB , author11=Turner, ST , author12=Fiehn, O , author13=Johnson, JA , author14=Kaddurah-Daouk, R, title=Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment., journal=PLOS ONE, volume=8, issue=3, doi=10.1371/journal.pone.0057639, pmid=23536766, pmc=3594230, pages=e57639 , year=2013, doi-access=free {{cite journal, last=Yerges-Armstrong, first=LM , author2=Ellero-Simatos S , author3=Georgiades A , author4=Zhu H , author5=Lewis JP , author6=Horenstein RB , author7=Beitelshees AL , author8=Dane A , author9=Reijmers T , author10=Hankemeier T , author11=Fiehn O , author12=Shuldiner AR , author13=Kaddurah-Daouk R, title=Purine Pathway Implicated in Mechanism of Resistance to Aspirin Therapy: Pharmacometabolomics-Informed Pharmacogenomics., journal=Clinical Pharmacology and Therapeutics, year=2013, doi= 10.1038/clpt.2013.119, volume=94, issue=4 , pages=525–532, pmc=4001726 , pmid=23839601 {{cite journal, last=Lewis, first=JP , author2=Yerges-Armstrong LM , author3=Ellero-Simatos S , author4=Georgiades A , author5=Kaddurah-Daouk R , author6=Hankemeier T, title=Integration of Pharmacometabolomic and Pharmacogenomic Approaches Reveals Novel Insights into Antiplatelet Therapy., journal=Clinical Pharmacology and Therapeutics, year=2013, doi=10.1038/clpt.2013.153, volume=94, issue=5 , pages=570–573, pmc=4116100 , pmid=23892404 {{cite journal, last1=Zhang, first1=S, last2=Nagana Gowda, first2=GA, last3=Ye, first3=T, last4=Raftery, first4=D, title=Advances in NMR-based biofluid analysis and metabolite profiling, journal=Analyst, year=2010, doi=10.1039/c000091d, pmid=20379603, volume=135, issue=7, pages=1490–8, pmc=4720135 {{cite journal, last=D'Adamo, first=P , author2=Ulivi, S , author3=Beneduci, A, title=Metabonomics and population studies age-related amino acids excretion and inferring networks through the study of urine samples in two Italian isolated populations., journal=Amino Acids, year=2010, volume=38, doi=10.1007/s00726-008-0205-8, pmid=19067108, issue=1, pages=65–73, s2cid=24205460 , display-authors=etal {{cite journal, last=Fan, first=TWM , author2=Yuan P , author3=Lane AN , author4=Higashi RM , author5=Wang Y , author6=Hamidi AB , author7=Zhou R , author8=Guitart Z , author9=Chen G , author10=Manji HK , author11=Kaddurah-Daouk R, title=Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions., journal=Metabolomics, year=2010, volume=6, issue=2 , pages=165–179, doi=10.1007/s11306-010-0208-9, pmc=2903070 , pmid=20631920 {{cite journal, last=Kaddurah-Daouk, first=R , author2=Bogdanov MB , author3=Wikoff WR , author4=Zhu H , author5=Boyle SH , author6=Churchill E , author7=Wang Z , author8=Rush AJ , author9=Krishnan RR , author10=Pickering E , author11=Delnomdedieu M , author12=Fiehn O, title=Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo, journal=Translational Psychiatry, year=2013, volume=3, doi=10.1038/tp.2012.142, issue=1, pages=e223, pmid=23340506 , pmc=3566722 , doi-access=free {{cite journal, last=Yao, first=JK , author2=Dougherty GG , author3=Reddy RD , author4=Matson WR , author5=Kaddurah-Daouk R , author6=Keshavan MS, title=Associations between purine metabolites and monoamine neurotransmitters in first-episode psychosis., journal=Frontiers in Cellular Neuroscience, year=2013, volume=7, issue=90 , page=90 , doi=10.3389/fncel.2013.00090 , pmid=23781173 , pmc=3678099, doi-access=free {{cite journal, last=Perroud, first=B , author2=Paymaan JN , author3=Gatchel JR , author4=Wang L , author5=Barupal DK , author6=Crespo-Barreto J , author7=Fiehn O , author8=Zoghbi HY , author9=Kaddurah-Daouk R, title=Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects., journal=PLOS ONE, year=2013, volume=8, issue=8, doi= 10.1371/journal.pone.0070610, pages=e70610 , pmid=23936457 , pmc=3732229, doi-access=free {{cite journal, last1=Yao, first1=JK, last2=Dougherty, first2=GG, last3=Reddy, first3=RD, last4=Keshavan, first4=MS, last5=Montrose, first5=DM, last6=Matson, first6=WR, last7=Rozen, first7=S, last8=Krishnan, first8=RR, last9=McEvoy, first9=J, last10=Kaddurah-Daouk, first10=R, title=Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia., journal=Molecular Psychiatry, year=2009, volume=15, issue=9, pages=938–953, doi=10.1038/mp.2009.33 , pmc=2953575, pmid=19401681 {{cite journal, last=Patkar, first=AA , author2=Rozen S , author3=Mannelli P , author4=Matson W , author5=Pae CU , author6=Krishnan RR , author7=Kaddurah-Daouk R, title=Alterations in tryptophan and purine metabolism in cocaine addiction: A metabolomic study., journal=Psychopharmacology, volume=206, issue=3, pages=479–489, doi=10.1007/s00213-009-1625-1 , year=2009, pmid=19649617 , s2cid=27979116 {{cite journal, last=Mannelli, first=P , author2=Patkar A , author3=Rozen S , author4=Matson WR , author5=Krishnan R , author6=Kaddurah-Daouk R, title=Opioid use affects antioxidant activity and purine metabolism: Preliminary results., journal=Human Psychopharmacology, year=2009, volume=24, issue=8, pages=666–675, doi=10.1002/hup.1068, pmc=3183957 , pmid=19760630 {{cite journal, last=Steffens, first=DC , author2=Jiang W , author3=Krishnan KR , author4=Karoly ED , author5=Mitchell MW , author6=O'Connor CM , author7=Kaddurah-Daouk R, title=Metabolomic differences in heart failure patients with and without major depression., journal=Journal of Geriatric Psychiatry and Neurology, year=2010, volume=23, issue=2, pages=138–146, doi=10.1177/0891988709358592, pmc=3279728 , pmid=20101071 {{cite journal, last1=Yao, first1=JK, last2=Dougherty, first2=GG Jr. , last3=Reddy, first3=RD, last4=Keshavan, first4=MS, last5=Montrose, first5=DM, last6=Matson, first6=WR, last7=McEvoy, first7=J, last8=Kaddurah-Daouk, first8=R, title=Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia, journal=PLOS ONE, volume=5, issue=3, doi=10.1371/journal.pone.0009508, pages=e9508, year=2010, pmid=20209081, pmc=2831068, doi-access=free {{cite journal, last=Condray, first=R , author2=Dougherty GG , author3=Keshavan MS , author4=Reddy RD , author5=Haas GL , author6=Montrose DM , author7=Matson WR , author8=McEvoy J , author9=Kaddurah-Daouk R , author10=Yao JK, title=3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia., journal= International Journal of Neuropsychopharmacology, year=2011, volume=14, issue=6 , pages=756–767, doi=10.1017/S1461145710001689 , pmid=21275080 , pmc=3117924 {{cite journal, last=Kaddurah-Daouk, first=R , author2=Rozen S , author3=Matson W , author4=Han X , author5=Hulette CM , author6=Burke JR , author7=Doraiswamy PM , author8=Welsh-Bohmer KA, title=Metabolomic changes in autopsy-confirmed Alzheimer's disease, journal=Alzheimer's & Dementia, year=2011, volume=7, issue=3, pages=309–317, doi=10.1016/j.jalz.2010.06.001, pmc=3061205 , pmid=21075060 {{cite journal, last=Han, first=X , author2=Rozen S , author3=Boyle SH , author4=Hellegers C , author5=Cheng H , author6=Burke JR , author7=Welsh-Bohmer KA , author8=Doraiswamy PM , author9=Kaddurah-Daouk R, title=Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics, journal=PLOS ONE, year=2011, volume=6, issue=7, doi=10.1371/journal.pone.0021643, pages=e21643 , pmid=21779331 , pmc=3136924, doi-access=free {{cite journal, last=Kaddurah-Daouk, first= R , author2=McEvoy J , author3=Baillie R , author4=Zhu H , author5=Yao J , author6=Nimgaonkar VL , author7=Buckley PF , author8=Keshavan MS , author9=Georgiades A , author10=Nasrallah HA, title=Impaired Plasmalogens in Patients with Schizophrenia, journal=Psychiatry Research, volume=198, issue=3, pages=347–52, doi=10.1016/j.psychres.2012.02.019 , year=2012, pmid= 22513041 , s2cid= 22582689 {{cite journal, author1=Yao JK , author2=Condray R , author3=Dougherty GG Jr. , author4=Keshavan MS , author5=Montrose DM , author6=Matson WR , author7=McEvoy J , author8=Kaddurah-Daouk R , author9=Reddy RD , title=Associations between purine metabolites and clinical symptoms in schizophrenia, journal=PLOS ONE, year=2012, volume=7, issue=8, doi=10.1371/journal.pone.0042165, pages=e42165 , pmid=22916123 , pmc=3419238, doi-access=free {{cite journal, last1=Kaddurah-Daouk, first1=R, last2=Zhu, first2=H, last3=Sharma, first3=S, last4=Bogdanov, first4=M, last5=Rozen, first5=SG, last6=Matson, first6=W, last7=Oki, first7=NO, last8=Motsinger-Reif, first8=AA, last9=Churchill, first9=E, last10=Lei, first10=Z, last11=Appleby, first11=D, last12=Kling, first12=MA, last13=Trojanowski, first13=JQ, last14=Doraiswamy, first14=PM, last15=Arnold, first15=SE, author16=Pharmacometabolomics Research Network, title=Alterations in metabolic pathways and networks in mild cognitive impairment and early Alzheimer's disease, journal=Translational Psychiatry, volume=3, doi=10.1038/tp.2013.18, issue=4, pages=e244, year=2013, pmid=23571809, pmc=3641405, doi-access=free {{cite journal, vauthors=Motsinger-Reif AA, Zhu H, Kling MA, Matson W, Sharma S, Fiehn O, Reif DM, Doraiswamy PM, Trajonowski JQ, Kaddurah-Daouk R, Arnold SE , title=Combining metabolomic and pathologic biomarkers for discriminating early Alzheimer's disease from normal cognitive aging, journal=Acta Neuropathologica Communications, volume=1, issue=28 {{cite journal, last=McEvoy, first=J , author2=Baillie RA , author3=Zhu H , author4=Buckley P , author5=Keshavan MS , author6=Nasrallah HA , author7=Yao J , author8=Kaddurah-Daouk R, title=Lipidomics reveals early metabolic changes in subjects with schizophrenia: effects of atypical antipsychotics, journal=PLOS ONE, volume=8, issue=7, doi=10.1371/journal.pone.0068717, pmid=23894336 , pmc=3722141 , pages=e68717 , year=2013, doi-access=free

External links

Genomics Directory
A one-stop biotechnology resource center for bioentrepreneurs, scientists, and students
Pharmacometabolomics Research Network (PMRN)

Human Metabolome Project
Project supported by Genome Alberta and Genome Canada
Metabolomics Society
An organization dedicated to promoting the growth, use and understanding of metabolomics in the life sciences.
Biological Magnetic Resonance Data Bank
A Repository for Data from NMR Spectroscopy on Proteins, Peptides, Nucleic Acids, and other Biomolecules
Scripps Center for Metabolomics and Mass Spectrometry
Branches of biology Metabolism