Last revised December 26, 2001
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Related glossaries include Applications Genomics, Sequencing  Technologies Microarrays, Biology Expression, Genetic Variations.

ADME: Abbreviation for Absorption, Distribution, Metabolism, Excretion. See also pharmacokinetics, drug disposition. [IUPAC Med Chem] Also referred to as ADME/ Tox ADME/ Toxicology). Related term pharmacokinetics.

biomarkers: 1. Parameter that can be used to identify a toxic effect in an individual organism and can be used in extrapolation between species. 2. Indicator signalling an event or condition in a biological system or sample and giving a measure of exposure, effect, or susceptibility.  [IUPAC Tox] 

biological marker (biomarker)  A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.  

Biomarkers may be particularly useful in early evaluations of the safety and efficacy of novel therapeutic interventions. Examples of these applications include in vitro studies in tissue samples, in vivo studies in animal models, and early-phase clinical trials to establish "proof of  concept." In addition to assessing therapeutic responses, biomarkers have several valuable applications in characterizing health and disease.

Safety evaluation has traditionally relied on the measurement of clinical chemistry and hematology parameters that serve as biomarkers of cellular integrity and homeostasis of the organism or as indicator of cell populations for damage, response, or as direct indicators of toxicity. Recently, advances in understanding the mechanisms of cellular and tissue damage, have created the opportunity to develop new surrogate endpoints of toxicity.

The optimal application of biomarkers is best served by a consensus in the use of terminology (Boissel, et al., 1992). Many terms are currently used such as surrogate markers, surrogate endpoints, intermediate endpoints, and others that have overlapping meanings. This ambiguity results from the involvement of people representing a variety of disciplines.  [NIEHS, US concept clearance for Biomarkers of Toxicity and Surrogate Endpoints for Safety, Feb.14-15, 2000] http://www.niehs.nih.gov/dert/council/2000/surro1.pdf

1. A pharmacological or physiological measurement which is used to predict a toxic event in an animal.  2. A specific biochemical in the body which has a particular molecular feature that makes it useful for measuring the progress of disease or the effects of treatment.  [Life Sciences]  Related terms surrogate markers  Genetic variations glossary biological markers; Broader term markers. 

chemoprediction: Involves predicting the response of a specific tumor to a range of chemotherapeutic agents. Utilizing genetic markers developed in the collaboration should allow cancer treatments to be selected on an individual patient basis, enabling physicians to select the most effective and least toxic chemotherapeutic agent for each patient. [Mayo Clinic and Millennium Predictive Medicine establish strategic alliance, press release Nov, 9, 1998] http://www.mlnm.com/news/1998/11-9--1.html

disease resistant individuals: Another interesting group [of phenotypes for pharmacogenomics] includes those who have no disease yet have high risk factors.  A classic example are individuals who exposed themselves to multiple risk factors for HIV - unprotected intercourse with multiple partners, intravenous drug use, etc. - and who either did not get the disease, or when they did get it, it progressed very slowly Interestingly , a gene target was identified in this group - the CCRX deletions.  There are many other disease- resistant groups in medicine. ... In general, disease- resistant groups provide a way of identifying given targets that are pre- validated in human subjects. [CHI Summit Pharmacogenomics]

drug metabolizing enzymes (DME) genes: The biochemical and transcriptional mechanisms by which drugs and xenobiotics affect the expression of the Phase I (cytochrome P450) and Phase II (e.g, glutathione S-transferase) drug metabolizing enzymes (DMEs). These important proteins are responsible for metabolizing endogenous compounds such as steroids, prostaglandins, and leukotrienes, as well as drugs and environmental pollutants. A notable characteristic of some DME genes is their ability to be transcriptionally upregulated by treatment with chemical  inducers such as phenobarbital (PB). [Jeff DeJong, Biology Dept. Univ. of Texas at Dallaas]  http://nsm1.utdallas.edu/bio/Dejong/dej99.html

drug response phenotype:SNPs are also useful in pharmacogenomics for matching an individual’s genotype with a drug- response phenotype. It is possible, in this context, to identify individuals who cannot adequately metabolize the drug and must be dosed accordingly, or those with a compromised drug target, who could not benefit from the drug. The discovery of such a relationship will require measuring hundreds of SNPs in or near candidate genes in several thousands of individuals. Validation will require detecting very few SNPs in several hundred to several thousand individuals. These relationships can be used either for clinical trials or diagnostically to determine therapy. Each clinical trial will involve measuring few SNPs in the low thousands of individuals. [CHI SNPs Update]

endocrine disrupters: Chemicals (usually environmental) that interfere with the endocrine (hormonal) systems of humans or animals. Frequently refers specifically to pesticides, herbicides, and fungicides that affect the reproductive system. The EPA may soon require further testing of EDs to determine their effects on human populations. [Xenogen website, Glossary] http://www.xenogen.com/glossary.html 

expression pharmacogenomics: Applies genome/proteome scale differential expression technologies to both in vivo and in vitro models of drug response to identify candidate markers correlative with and predictive of drug toxicity and efficacy. It is anticipated to streamline drug development by triaging towards lead compounds and clinical candidates that maximize efficacy while minimizing safety risks. [Bonnie E. Gould Rothberg "Use of animal models in expression pharmacogenomic analysis" (Pharmacogenomics Journal 1: 48-58, 2001) Selected abstracts, CuraGen Corp. US] http://www.curagen.com/corporate/published_paper.htm

functional proteomics: Proteomics glossary

genotype: Genomics glossary  Related terms Sequencing glossary

influence-based data mining: Algorithms & data management glossary  for relevance of this technique to pharmacogenomics data.

kinetic outliers: Intersubject variability - in particular, the presence of kinetic outliers - is encountered during the course of a drug development program. Often, these outliers can be explained by genetic variability or polymorphism in cytochrome CYP450 genes responsible for drug metabolism. Genetic analysis of outliers could help explain the variability in metabolism and possibly influence the development and labeling of the drug in question. [CHI Summit Pharmacogenomics] Related term pharmacokinetics

lure of initial value: Drug approvals glossary

markers: Genetic variations glossary

mechanism of action: A more detailed, molecular description of events. [Genetic Toxicology Association, Spring 2000 meeting  report] http://www.ems-us.org/gta/springr00.html 

The knowledge of mechanisms of action is important for two reasons: (1) you need secondary assays that are really associated with a mechanism of action in order to optimize leads in the best possible way, and (2) the FDA will increasingly require that you know the mechanism of action, before you go into clinical trials, to prevent possible toxic side effects. ... The good news is that an increasingly large percentage of drugs that are going through the pipeline now have known mechanisms of action (MOAs) at a molecular level, which is a contrast to 10 to 20 years ago. We now are understanding how therapies interact with the human body and with disease on a much more detailed level. Most drugs now have known targets, and most targets participate in known pathways. The caveat to that, as I mentioned earlier, is that biology is very complicated, and we’re learning that the target isn’t enough. It’s not enough to simply know that a certain molecule binds to a certain protein and turns it off. What you really need to know about are the pathways, and the side pathways, and the domains, and the homologous targets [CHI Breaking Bottlenecks]

 Broader term mode of action.

mode of action MOA: Examples of MOAs that are usually encountered include mutagenicity, mitogenesis, inhibition of cell death, immune suppression, among others. [Genetic Toxicology Association, Spring 2000 meeting report] http://www.ems-us.org/gta/springr00.html

The key obligatory process governing the action of chemicals without the level of detail required to determine mechanism of action. Comparison of gene expression fingerprints of individual chemicals from many mode- of- action classes (for example, cytotoxic chemicals, peroxisome proliferators, or estrogenic chemicals) will allow the identification of common sets of genes (a gene profile) whose expression at multiple doses and times of exposure is consistently linked to particular kinds of exposure and particular disease outcomes. [Chemical Industry Institute of Toxicology "Use of microarrays in toxicology" 1999]  Narrower term: mechanism of action http://www.ciit.org/toxicogenomics/microarraysintoxicology.html

molecular toxicology: Very different to "classical toxicology" and involves defining individual susceptibility to drugs and toxins and the science of pharmacogenetics. This discipline relies heavily on molecular techniques, information generated by the human genome project and a new initiative at the National Institute of Health Sciences, the Environmental Genome Project. Since many of us in the Pharmacy School have an interest in drugs and their adverse effects, the mechanistic aspects of drug induced toxicity is an area of emphasis. If one doesn’t understand the mechanisms underlying drug toxicity it is not possible to prevent or ameliorate toxicity or design rational antidotal therapies. Environmental toxicity and carcinogenesis continue to be major areas of regulatory and public concern. [Dept. of Pharmaceutical Science, Univ. of Colorado School of Pharmacy "From the Chair" 2001] http://www.uchsc.edu/sp/sp/DOPS/dops.html

personalized medicine: Approaches in the emerging field of personalized medicine will allow clinicians to predict the risk of disease based on genetic testing, the likelihood that a particular therapy will be effective in a particular patient, the risk of an adverse effect, and the probable course of a disease. The technologies underlying these new approaches will change drug discovery and development, clinical trials, diagnosis and treatment of disease, and the structure of the world pharmaceutical market.  This report reviews the disease areas that personalized medicine will impact, and when and how this approach will first start influencing diagnosis and treatment in these indications and explores the commercial impact of personalized medicine and identifies the business models most likely to lead to success in this field. [CHI reports Personalized Medicine; Revolutionizing Health Care Through New Diagnostics and Patient- Tailored Treatments, Jan. 2002] http://www.chireports.com/content/reports/predictive_medicine.asp

pharmacodynamics: Study of the biochemical and physiological processes determining the effects of drugs on organisms. Narrower term pharmacokinetics Related terms ADME, mechanism of action, mode of action

pharmacogenetics: A subset of pharmacogenomics encompassing the study of genetic variation underlying differential response to drugs, particularly genes involved in drug metabolism.  [CHI SNPs]. From pharmacology + genetics. Broader term pharmacogenomics.

With the implementation of pharmacogenetics, diseases will be evaluated by mechanisms, rather than just symptoms, and early response will be based on prognosis and susceptibility rather than just diagnosis. It will introduce a bottom- up approach to disease, which will be defined in terms of its heterogeneity, and not "averaged out" to conform to a uniform model. [CHI Summit Pharmacogenomics]

The terms "pharmacogenomics" and "pharmacogenetics" are often interchanged and used without clear definition. For the purpose of this meeting, I will use working definitions. Pharmacogenetics refers to people including gene identification and "right medicine for right patient." Pharmacogenomics refers to the application of tools including, but not limited to, the functional genomics toolbox of differential gene expression (DGE), proteomics, yeast 2- hybrid (Y2H) analyses, tissue immuno- and histopathology, etc. There are two applications of pharmacogenetics that may use similar techniques but are quite distinct: a) susceptibility gene identification and b) "right medicine for right patient" . [Allen D. Roses "Pharmacogenetics and pharmacogenomics in the discovery and development of medicines " Pharmacogenetique et Pharmacogenetique, Institut Pasteur, Paris [France], 12-13 Octobre 2000, Institut Pasteur] See also Proteomics glossary. http://www.pasteur.fr/applications/euroconf/pharmaco/pharmaco-prog.html

Pharmacogenetics Links
Pharmacogenetics Initiatives, NIGMS, US  http://www.nigms.nih.gov/funding/pharmacogenetics.html

pharmacogenomics: The objective of pharmacogenomics is ultimately to target drugs specifically to those patients with a genetic make- up (genotype) such that they will have close to 100% response with no side effects. The real long- term potential for pharmacogenomics is to stratify diseases by mechanism and develop therapies, or even preventative approaches, based on genetic risk factors. More immediately, pharmacogenomics can be used to improve the clinical development processes. [CHI Summit Pharmacogenomics]

Coding variation has a direct impact on how the body handles drugs. What is of greater commercial significance is the extent to which this information should be sought after and employed in rational drug design and delivery. We now witness accumulating evidence that the "red in tooth and claw" market will be the final and enduring arbiter, as both pharmaceutical companies and government invest in Hap Map projects, and the like. As the technology moves out of the lab and into mainstream culture we must also note that current state of the art in genetics- based clinical safety/ efficacy monitoring, routinely underutilizes such obvious molecular assessments as gender and race profiling in clinical trials. Thus, it is likely to be many years before the 'new and improved' molecular tests can be implemented on a wide- scale basis.   Pharmacogenomics/Pharmacoproteomics Europe May 15- 16, 2002, Munich, Germany 

One of the big question marks in genomics. Interest in this field is very high among companies offering or developing the types of tools and services that will be needed if this field catches on. These offerings include software, pharmacogenomic tests, new drugs based on pharmacogenomic information, secure genotype banks, Web- based clinical trials, and genotype data. But it is not yet clear how broad the impact of pharmacogenomics will be. Can these studies actually be done for enough diseases? Will enough diseases have a stronger genetic than environmental component, and will SNPs be generally useful to find genetic associations?  [CHI Bioinformatics]

From pharmacology + genomics. Narrower term pharmacogenetics

pharmacogenomics technologies: The most critical technology is high throughput genotyping (both for large numbers of samples to be genotyped for a few variants, and a smaller number for fuller sequencing of  a large number of variants).

pharmacokinetics: Process of the uptake of drugs by the body, the biotransformation they undergo, the distribution of the drugs and their metabolites in the tissues, and the elimination of the drugs and their metabolites from the body. Both the amounts and the concentrations of the drugs and their metabolism are studied. The term has essentially the same meaning as toxicokinetics but the latter term should be restricted to the study of substances other than drugs. [IUPAC Compendium]

pharmacoproteomics: Use of protein expression data to predict toxicity and understand drug mode of action. [CHI, Proteomics] 

placebo non-responders: Drug approvals glossary

placebo responders: Drug approvals glossary

population genetics, population genomics: Genetic variations glossary

predictive medicine: Various approaches, including pharmacogenomics, that make up the emerging field of predictive medicine. These approaches allow clinicians to predict the risk of disease based on genetic testing, whether a particular therapy will be effective in a particular patient, the risk of an adverse effect, and the risk that a disease will progress in a particular manner. The technologies underlying these new approaches will change drug discovery and development, clinical trials, and diagnosis and treatment of disease. [CHI Predictive Pharmacogenomics] 

stratification: Drug approvals glossary

structural pharmacogenomics: Applying structural genomics toward understanding the consequences of  single nucleotide polymorphisms [SNPs] [CHI Summit Pharmacogenomics].

surrogate endpoint: A biomarker intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Surrogate endpoints are a subset of biomarkers. While all surrogate endpoints are biomarkers, it is likely that only a few single biomarkers will be considered for use as surrogate endpoints. [NIEHS, US Concept Clearance for Biomarkers of Toxicity and Surrogate Endpoints for Safety, Feb. 14-15, 2000]  Related terms biomarkers, surrogate marker.  http://www.niehs.nih.gov/dert/council/2000/surro1.pdf

Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important. For example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of  important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up. [Clarke M, Oxman AD, editors. Cochrane Reviewers Handbook 4.1.1 [updated December 2000]. In: The Cochrane Library, Issue 4, 2000. Oxford: Update Software. Updated quarterly.] http://www.cochrane.dk/cochrane/handbook/hbookSurrogate_endpoints.htm

surrogate marker: A laboratory measurement of biological activity within the body that indirectly indicates the effect of treatment on disease state. CD4 cell counts and viral load are examples of surrogate markers in HIV infection. [GMHC Treatment Issues AIDS Medical Glossary, 1995]  http://www.critpath.org/research/gmhgloss.htm  Related terms biomarkers, surrogate endpoint.

susceptibility: Clinical genomics glossary 

target haplotype: Pharmacogenomics can reduce risk when used toward identifying the haplotypes of a target gene. For example. there are some beta agonists that have differential effects on haplotypes of the beta-1 receptor. In fact, some have absolutely no effect on at least one haplotype of the receptor. Uncovering such differences can reveal the degree to which a candidate compound will vary in its efficacy, and will help identify sub- populations that may benefit from the drug and others which may not benefit... In the few cases where a haplotype effect has been demonstrated, the discovery was accidental, occurring after the development of the drug. [CHI Summit Pharmacogenomics]

tox-chips: Developed at NIEHS [National Institute for Environmental Health Sciences, US], which contains copies, or clones, of about 2,000 of the 80,000 genes in the human body. Millions of  cloned copies of each gene form a nearly invisible dot that is "arrayed" - hence the name - in a grid pattern on the glass slide. The [NIEHS Microarray] center [at Research Triangle Park, NC] also uses an even newer microarray, called the Human ToxChip, containing clusters of each of  12,000 different cloned genes.

Toxic substances produce changes that express, or turn on and off, genes, the center  scientists said, and the chips and the accompanying computer support used to read the slides, take advantage of that linkage.  Initially the new center is evaluating known toxins - for example, chemicals that are known to cause cancer and/or mutations - to build a library or database showing the typical genetic changes that these known poisons produce. Once they have "signature" profiles of how known toxins change genes, the scientists said, they can evaluate other chemicals for potential harm by comparing the gene changes they produce with those made by the known toxins. [NIEHS "Environmental Health Institute to Use Gene Chips to Evaluate Chemicals for Potential Harm to Humans" Feb. 29, 2001]  http://www.niehs.nih.gov/oc/news/toxchip.htm

Uses information from the Human Genome Project (HGP) to construct genetic "probes" on the chip that differentiate genes activated by toxicants from genes that are active under normal conditions. [NIEHS, US "National Center for Toxicogenomics to Study Genetic Basis of Disease Caused by Environmental Pollution" Dec. 7, 2000] http://www.niehs.nih.gov/nct/pr07de00.htm

Related terms Microarrays glossary

toxicogenomics: The effects of chemical exposure on populations. [National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project] http://www.niehs.nih.gov/envgenom/     From toxicology + genomics

Assumes that gene expression must be altered during toxicity. The transcription profile seen after treatment with a specific toxin is considered a signature for that agent. Toxicogenomics holds that unknown compounds that elicit a similar transcription profile may have similar biological effects. Toxicity- induced alterations in the pattern of gene expression may involve induction, repression, or stabilization/ destabilization of mRNAs of many different classes…Study of chemically induced gene expression patterns and comparison to signatures of well-characterized toxins also provide information about the mechanisms underlying toxic effects. [A Francis "Toxico-logic" Scientist 14 (1): 18 Jan 10, 2000] http://www.the-scientist.com/yr2000/jan/profile_000110.html

toxicokinetics: Process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and the elimination of the substances and their metabolites from the body. Both the amounts and the concentrations of the substances are studied. The term has essentially the same meaning as pharmacokinetics, but the latter term should be restricted to the study of pharmaceutical substances. [IUPAC Compendium]

toxicoproteomics: Proteomics glossary

validation - drug response phenotype: See under drug response phenotype.

xenobiotic metabolizing enzymes: Interindividual variability in drug and/or xenobiotic metabolism can be determined by several different factors but the existence of genetic polymorphisms in the genes encoding metabolizing enzymes and probably, more rarely, in genes encoding transcription factors that regulate the expression of genes encoding metabolizing enzymes, are important factors. Pharmacogenetic polymorphisms in genes encoding xenobiotic- metabolizing enzymes may have a variety of effects, depending on both type of reaction catalyzed and the type of substrate [Kouza, Dept. of Toxicology, Toyama Medical and Pharmaceutical Univ.] Related term xenobiotic Drug discovery & Development glossary http://www.toyama-mpu.ac.jp/ph/cliche2/kouza-e.html

Bibliography

[CHI Predictive Pharmacogenomics] CHI Genomic Report, Jan. 2002.

[CHI Summit Pharmacogenomics] Pharmacogenomics: Finding the competitive edge in genetic variations, Mike Silver, May 2001 

[CHI Predictive Medicine] Predictive Medicine:  Revolutionizing Health Care Through New Diagnostic Approaches and Patient- Tailored Treatments, August 2001.  

[IUPAC Toxicology] International Union of Pure and Applied Chemistry, GLOSSARY FOR CHEMISTS OF TERMS USED IN TOXICOLOGY Clinical Chemistry Division, Commission on Toxicology, Recommendations. Pure and Appl. Chem., 65 ( 9):  2003-2122, 1993. 1200+ definitions.   http://sis.nlm.nih.gov/main.htm

Alpha glossary index

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.