A

ABC transporters ↑ Back to the top

ATP-binding cassette transporters are a family of transmembrane proteins that function in the transort of a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs.  ABC transporters are involved in tumor resistance, cystic fibrosis, bacterial multidrug resistance and a range of other inherited human diseases.

ADME ↑ Back to the top

ADME is a common acronym for absorption, distribution, metabolism and excretion. ADME studies are among a series of non-clinical safety studies conducted prior to human clinical trials. These studies are part of the evaluation to characterize a drug candidate under the conditions of the supported clinical trial.

AhR ↑ Back to the top

Aryl hydrocarbon receptor. AhRs mediate the induction of CYP1A enzymes by agents such as b-naphthoflavone, 3-methylcholanthrene, Aroclor 1254 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

aliquot ↑ Back to the top

A portion obtained by dividing the whole into several parts, especially one of two or more samples of a substance that have the same volume or weight.

allelozyme ↑ Back to the top

An allelic (genetic) variant of an enzyme. The term was first used to describe variants of alcohol dehydrogenase, but may be applied to other enzymes.

antibody ↑ Back to the top

A protein produced by B lymphocytes in response to, and interacting specifically with, an antigen. This antigen-antibody reaction forms the basis of immunity, and is exploited in various immunoassays. (Also see IgG.)

antigen ↑ Back to the top

A substance, usually a protein, that is recognized by the immune system as foreign and that can elicit an immune response, resulting in production of an antibody.

assay ↑ Back to the top

The analysis of a substance or mixture to determine its constituents and the relative proportions of each. This term is synonymous with “test”.

B

biotransformation ↑ Back to the top

The process by which xenobiotics are chemically modified and converted to water-soluble metabolites that can be readily excreted. Biotransformation is often called metabolism, although the latter term has a broader definition (see metabolism). The process of biotransformation is divided into two phases called Phase I (oxidation and hydrolysis) and Phase II (conjugation).

blood brain barrier ↑ Back to the top

The blood brain barrier (BBB) is the specialized system of capillary endothelial cells that protects the brain from harmful substances in the blood stream, while supplying the brain with the required nutrients for proper function. Unlike peripheral capillaries that allow relatively free exchange of substances across or between cells, the BBB strictly limits transport into the brain through both physical (tight junctions) and metabolic (enzymes) barriers. Thus the BBB is often the rate-limiting factor in determining permeation of therapeutic drugs into the brain. Additionally, BBB breakdown is theorized to be a key component in central nervous system associated pathologies. BBB investigation is an ever-growing and dynamic field studied by pharmacologists, neuroscientists, pathologists, physiologists, and clinical practitioners

C

CAR ↑ Back to the top

Constitutive androstane receptor. CARs mediate the induction of CYP2B enzymes by agents such as phenobarbital, antihistamines and Aroclor 1254. 

clearance ↑ Back to the top

The volume of blood or plasma that is cleared of a substance per time unit through elimination processes.

CMV ↑ Back to the top

Cytomegalovirus

coenzyme ↑ Back to the top

A substance needed by certain enzymes to catalyze reactions. Most vitamins are considered coenzymes.

cofactor ↑ Back to the top

A substance that functions as a co-substrate in an enzyme-catalyzed reaction. For example, NADPH is a cofactor for cytochrome P450-catalyzed reactions.

CYP ↑ Back to the top

Cytochrome P450

Cytochrome P450 ↑ Back to the top

Cytochrome P450 (CYP) is a family of membrane-bound hemeproteins that play a key role in the oxidative biotransformation of drugs and a variety of other xenobiotics and endobiotics.

Cytomegalovirus ↑ Back to the top

Cytomegalovirus (CMV) is a herpesvirus that infects directly through mucous membrane contact or via tissue transplant or blood transfusion. Approximately half the adult population in developed countries, and three-quarters of HIV risk groups have been infected with CMV.

cytosol ↑ Back to the top

A subcellular fraction that represents the soluble portion of liver homogenate, and contains numerous drug-metabolizing enzymes, especially those involved in Phase II biotransformation, such as sulfotransferases and glutathione S-transferases.

D

DMEM ↑ Back to the top

Dulbecco’s Modified Eagle Medium. DMEM is cell culture medium designed for supporting the growth of a broad spectrum of cell lines.

E

EDTA ↑ Back to the top

Ethylenediaminetetraacetic acid.

ELISA ↑ Back to the top

Enzyme-linked immunosorbent assay. A microtiter-based, immunochemical technique to detect and quantitate levels of a protein with an antibody against that protein (Antigen).

EM ↑ Back to the top

Extensive metabolizer. A term used to distinguish individuals who express an enzyme from those who, for genetic reasons, do not. The latter individuals are known as PM, for poor metabolizers.

endobiotic ↑ Back to the top

An endogenous substance, as opposed to a xenobiotic (a foreign substance). The same hepatic enzymes that biotransform xenobiotics (such as drugs) also biotransform certain endobiotics (such as steroid hormones).

endoplasmic reticulum ↑ Back to the top

Intracellular membranes that contain cytochrome P450 and other drug-metabolizing enzymes. During tissue homogenization, the endoplasmic reticulum vesiculates and forms microsomes.

enterocyte ↑ Back to the top

A type of intestinal epithelial cell.  The majority of metabolic enzymes within the intestine are contained in the mature enterocytes found at the apices of the intestinal villi.

enzyme mapping ↑ Back to the top

See Reaction Phenotyping.

enzymes ↑ Back to the top

Biological catalysts (proteins) that speed up chemical reactions.

ex vivo ↑ Back to the top

A combination of in vivo and in vitro techniques whereby animals are treated in vivo, followed by an in vitro analysis of the effects of the treatment.

extrahepatic ↑ Back to the top

Organs and tissues other than the liver. Non-hepatic drug metabolism is often called extrahepatic metabolism.

F

facilitative transporters ↑ Back to the top

SLC transporters that allow solutes to flow with their electrochemical gradients

FDA ↑ Back to the top

Food and Drug Administration

first-pass metabolism ↑ Back to the top

This refers to drugs that enter the portal blood supply after they are absorbed from the small intestine and are exposed to metabolic enzymes in the liver. If a large portion of the drug is metabolized in this first pass through the liver, then only a smaller portion of the absorbed dose will enter into the systemic circulation.

FMO ↑ Back to the top

Flavin monooxygenase. A microsomal enzyme that catalyzes heteroatom oxygenation of xenobiotics.

G

GLP ↑ Back to the top

Good Laboratory Practice
For more information, refer to XenoTech's poster A Comparison of Regulatory Requirements (PDF).

H

half life ↑ Back to the top

The time it takes for a measurable quantity, such as a drug concentration, to decrease by half of its initial value and is expressed in units of time, e.g. hours.

hepatic ↑ Back to the top

Pertaining to the liver.

Hepatitis ↑ Back to the top

A viral infection of the liver, which may be called by hepatitis A, B or C.

hepatocytes ↑ Back to the top

The main cell type in the liver (parenchymal cell). Hepatocytes can be used to study the metabolism of drug candidates and their ability to induce (up-regulate) or suppress (down-regulate) CYP enzyme expression. Freshly isolated (primary culture) or cryopreserved hepatocytes are used for drug metabolism studies; whereas, primary cultures of hepatocytes are used for enzyme induction studies.

HIV ↑ Back to the top

Human Immunodeficiency Virus; the cause of Acquired Immunodeficiency Syndrome (AIDS).

homogenate ↑ Back to the top

Material that has been homogenized. A liver homogenate is prepared by mechanical disruption of the cells resulting in the release of organelles (subcellular fractions).

homogeneous ↑ Back to the top

Of uniform structure or composition throughout.

homogenize ↑ Back to the top

A process that, in our application, involves breaking apart cells from tissue such as liver, releasing organelles and cytoplasm.

hormone ↑ Back to the top

A substance originating in an organ or gland that is conveyed through the blood to another part of the body, stimulating it by chemical action to regulate functional activity or to increase secretion of another hormone. Many steroid hormones are substrates for drug-metabolizing enzymes.

HPLC ↑ Back to the top

High performance liquid chromatography. (Also known as, high pressure liquid chromatography.)

hydrophilic ↑ Back to the top

Literally: “water-loving.” Fat-soluble (lipophilic) xenobiotics are generally biotransformed to water soluble (hydrophilic) metabolites.

hydrophobic ↑ Back to the top

Literally: “fear of water.” Synonymous with lipophilic. Can be used to describe substances that are not water soluble. Most drugs are hydrophobic(lipophilic), and are converted to water-soluble hydrophilic metabolites by biotransforming enzymes.

I

IC50 ↑ Back to the top

Concentration of inhibitor at which 50% of the turnover of a single concentration of a form-selective substrate is inhibited.

IgG ↑ Back to the top

Immunoglobulin G; one of the major classes of antibodies. (The others are IgA, IgE and IgM). IgG is the major antibody produced after prolonged or repetitive exposure of an animal to an antigen (or immunogen).

immunogen ↑ Back to the top

See Antigen.

in vitro ↑ Back to the top

A biological process made to occur in a laboratory vessel or other controlled experimental environment rather than within a living organism or natural setting.

in vivo ↑ Back to the top

Literally, “in life.” An experiment conducted with a living organism (such as a laboratory animal).

inducer ↑ Back to the top

A compound that increases (up-regulates) the levels of cytochrome P450 and/or other drug-metabolizing enzymes.

induction ↑ Back to the top

The process whereby a chemical increases (up regulates) the levels of cytochrome P450 and/or other drug-metabolizing enzymes.

inhibition ↑ Back to the top

A decrease in enzyme activity. Note: a decrease in actual enzyme levels is called suppression.

inhibitor ↑ Back to the top

A compound that decreases the activity of an enzyme.

K

K inact ↑ Back to the top

The rate at which an irreversible enzyme-inhibitor complex is formed, inactivating the enzyme in question.

Kansas Governor's Exporter of the Year Award ↑ Back to the top

This award recognizes Kansas companies that have demonstrated exceptional marketing prowess outside the United States.  The Trade Development Division and Kansas International Trade Coordinating Council (KITCC), comprising public and private business entities, jointly operate the program. 

Ki ↑ Back to the top

Dissociation constant of the enzyme-inhibitor complex.

Km ↑ Back to the top

The substrate concentration at ½ maximal velocity.

L

lipophilic ↑ Back to the top

Having an affinity for, tending to combine with, or capable of dissolving in lipids.

M

MAO ↑ Back to the top

Monoamine Oxidase. A flavin-containing enzyme located on the outer membrane of the mitochondria. There are two forms of monoamine oxidase (MAO A and MAO B), both of which are involved in the Phase I biotransformation of certain drugs.

MDR ↑ Back to the top

Multi-Drug Resistance

mechanism-based inhibition ↑ Back to the top

Often used to refer to any irreversible or quasi-irreversible metabolism-dependent inhibition caused by substrates that are converted to one or more products that immediately and irreversibly inactivate the enzyme and do not leave the active site during catalysis by the enzyme. By definition, mechanism-based inhibition excludes the formation of metabolites that are simply more potent direct-acting inhibitors than the parent.

metabolism ↑ Back to the top

The total fate of a xenobiotic, which includes: absorption, distribution, biotransformation, metabolism and elimination (ADME). Metabolism and biotransformation are often used interchangeably, but the latter term does not encompass absorption, distribution and elimination.

metabolism-dependent inhibition ↑ Back to the top

includes both mechanism-based inhibition and also the formation of metabolites that are more potent direct-acting inhibitors than the parent (i.e., reversible metabolism-dependent inhibition).

microsomes ↑ Back to the top

Vesicles derived from the endoplasmic reticulum, which contain cytochrome P450 enzymes that are responsible for many phase I biotransformation reactions. Microsomes are isolated by ultracentrifugation (104,000 g for one hour) of the postmitochondrial (S9) fraction.

mitochondria ↑ Back to the top

Organelles that synthesize ATP and largely determine cellular respiration rate. This subcellular fraction is well suited for determining the metabolism of certain xenobiotics by such mitochondrial enzymes as monoamine oxidase (MAO), rhodanese, N-acyltransferase and aldehyde dehydrogenase.

monoclonal ↑ Back to the top

Antibodies that are identical because they were produced by one type of immune cell and are all clones of a single parent cell.

mRNA ↑ Back to the top

Messenger Riboneucleic Acid (mRNA) is a molecule of RNA encoding a chemical 'blueprint' for a protein product.  Branched DNA assays can be used to detect the presence of mRNA.

N

NCE ↑ Back to the top

New chemical entity

NME ↑ Back to the top

New molecular entity

O

OECD ↑ Back to the top

Organisation for Economic Co-operation and Development

P

P-gp ↑ Back to the top

P-Glycoprotein. A human ABC transporter also known as MDR1 or ABCB1. It is extensively distributed and expressed in normal cells such as those lining the intestine, liver cells, renal proximal tubular cells, and capillary endothelial cells comprising the blood-brain barrier.

Percoll® ↑ Back to the top

Colloidal PVP-coated silica used for density-gradient centrifugation of cells, viruses and subcellular particles.

perpetrator ↑ Back to the top

a drug that alters the clearance of a victim drug

pharmacokinetics ↑ Back to the top

Study of the intake of drugs in the body including absorbtion, distribution, transformation and excretion.

Phase I ↑ Back to the top

Biotransformation, involves hydrolysis, reduction, and oxidation. These reactions expose or introduce a functional group. Many times, this is the rate-determining step of biotransformation.

Phase II ↑ Back to the top

Biotransformation, involves glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione and conjugation with amino acids. Promotes the excretion of foreign chemicals.

PM ↑ Back to the top

Poor metabolizer. A term used to distinguish individuals who, for genetic reasons, do not express an enzyme from those who do. The latter individuals are known as EM, for extensive metabolizers.

polyclonal ↑ Back to the top

Arising from more than one cell. Polyclonal antibodies are derived from animal antisera and contain a variety of antibodies that often recognize multiple antigenic determinants on an immunogen.

polymorphism ↑ Back to the top

Genetic variation. An enzyme that is expressed in some individuals but not others is said to be a polymorphic enzyme, as are enzymes that are encoded by the same gene locus but differ by one or more amino acids. These latter enzymes are also known as allelic variants or allelozymes.

PPARa ↑ Back to the top

The receptor (DNA-binding protein or transcription factor) that mediates the induction of CYP4A enzymes by clofibrate and other peroxisome proliferators. PPARa stands for peroxisome proliferator-activated receptor.

proteins ↑ Back to the top

Large molecules formed from amino acids linked by peptide (amide) bonds. Some proteins are glycosylated (linked to carbohydrates) or modified with other substances.

PXR ↑ Back to the top

The receptor (DNA-binding protein or transcription factor) that mediates the induction of CYP3A enzymes by agents such as rifampin (human) and pregnenolone-16a-carbonitrile (rodents). PXR stands for pregnane X receptor.

Q

qRT-PCR ↑ Back to the top

Reverse transcription followed by quantitative polymerase chain reaction analysis

R

reaction phenotyping ↑ Back to the top

Regulatory authorities encourage the identification of the specific enzyme(s) involved in the clearance of a drug, a process known as reaction phenotyping or enzyme mapping. This information is useful for predicting pharmacokinetic variability and adverse drug reactions.

rhabdomyolysis ↑ Back to the top

The rapid breakdown of skeletal muscle tissue due to traumatic injury, either mechanical, physical or chemical.

S

S9 ↑ Back to the top

The post-mitochondrial supernatant fraction, which is prepared by subjecting tissue homogenate to centrifugation at 12,000 g. This subcellular fraction contains both cytosol and microsomes, and is well suited for determining the profile of metabolism of xenobiotics in humans or animals because it contains enzymes involved in both phase I and II biotransformation

secondary active transporters ↑ Back to the top

SLC transporters that allow solutes to flow against their electrochemical gradient by coupling to transport of a second solute that flows with its gradient, such that the overall free energy change is favorable

SLC transporters ↑ Back to the top

Solute carrier transport proteins, mainly located in the outer cell membrane; however, some members of this group are located in mitochondria or other intracellular organelles.   SLC transporters include proteins that are facilitative transporters and secondary active transporters.

SOP ↑ Back to the top

Standard operating procedure

substrate ↑ Back to the top

The substance acted upon by an enzyme.

SULT ↑ Back to the top

Sulfotransferase. Phase II enzymes that catalyze the sulfation of xenobiotics. Note: The reaction catalyzed by these enzymes is actually one of sulfonation, for which reason SULTs are also known as sulfonotransferases.

T

time-dependent inhibiton ↑ Back to the top

This is a general term used to refer to any increase in inhibitory potential that occurs as an enzyme is exposed to an inhibitor over time, and does not necessarily require a metabolic step. Time-dependent inhibition may include the following:

1. slow-binding inhibition
2. inhibition by a degradation product (i.e., non-enzymatic conversion to an inhibitory species
3. reversible metabolism-dependent inhibition
4. irreversible metabolism-dependent inhibition

 

Trypan Blue ↑ Back to the top

Large molecular weight cellular dye, which is taken up exclusively by cells with compromised membranes (non-viable cells). It is used in determining viability of a cell preparation. Due to its size, the dye cannot penetrate and will not color live cells.

U

UGT ↑ Back to the top

UDP-Glucuronosyltransferase. Phase II enzymes that catalyze the glucuronidation of xenobiotics.

V

victim ↑ Back to the top

a drug that is the object of drug-drug interactions

Vmax ↑ Back to the top

The maximum rate of a reaction.

W

Western immunoblotting ↑ Back to the top

An immunochemical technique in which proteins are separated by SDS-polyacrylamide gel electrophoresis, transferred to a nylon membrane (or equivalent) and probed with an antibody to locate the protein of interest.

X

xenobiotics ↑ Back to the top

Foreign chemicals which can be both man-made and natural chemicals, such as drugs, pesticides, pollutants, alkaloids, and many others.