Bioavailability

• Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
• Bioavailability of a drug is largely determined by the properties of the dosage form, which depend partly on its design and manufacture. Differences in bioavailability among formulations of a given drug can have clinical significance.

Caco-2 Permeability

• Caco-2 cells are a human colon epithelial cancer cell line used as a model of human intestinal absorption of drugs and other compounds.
• In many respects, the Caco-2 cell monolayer mimics the human intestinal epithelium. Caco-2 are used for the determination of the concentration of test compounds and the computation of the rates of permeability for each compound (called the apparent permeability coefficients).

HIA

• When a drug is orally administered, it needs to be absorbed from the human gastrointestinal system into the bloodstream of the human body. This ability of absorption is called human intestinal absorption (HIA) and it is crucial for a drug to be delivered to the target.

HOB

• Human oral bioavailability (HOB) is an important pharmacokinetic parameter that measures the amount of a drug that actually enters circulation within the body after ingestion.
• Higher HOB of the drug can reduce the amount of administration required to achieve the expected pharmacological effect because it can reduce the side effects and toxicity risks brought by the drug.

MDCK Permeability

• Madin-Darby Canine Kidney (MDCK) cells are used to evaluate the permeability of compounds across the human intestinal barrier.
• MDCK cells have high polarity and tight junctions, which can mimic the characteristics of human intestinal epithelial cells.

PAMPA

• PAMPA (parallel artificial membrane permeability assay) is a commonly employed assay to evaluate drug permeability across the cellular membrane.
• PAMPA is a non-cell-based, low-cost and high-throughput alternative to cellular models. Although PAMPA does not model active and efflux transporters, it still provides permeability values that are useful for absorption prediction because the majority of drugs are absorbed by passive diffusion through the membrane.

Pgp Inhibitor / Substrate

• P-glycoprotein (Pgp) is an ABC transporter protein involved in intestinal absorption, drug metabolism, and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety.
• Inhibitors with IC50 values lower than 15 μM may be involved in drug-drug interactions, whereas those with an IC50 value higher than 100 μM are considered noninhibitors. Molecules having an IC50 value between 15 and 100 μM are classified as weak inhibitors.

BBB Penetration

• The Blood-Brain Barrier (BBB) is a membrane that separates circulating blood and the brain extracellular fluid.
• Some of the main functions of this barrier comprise the protection of the brain from foreign substances in the blood that may injure it, protection against hormones and neurotransmitters in the rest of the body, and maintenance of a constant environment for the brain.

PPB

• The human plasma protein binding (PPB) is expressed as the percentage of a drug bound to plasma proteins in the blood. This rate strongly affect a drug's efficiency of delivery. The less bound a drug is, the more efficiently it can traverse and diffuse to the site of actions. From a ChEMBL assay deposited by AstraZeneca.

VD

• Volume Distribution (VD) is a theoretical concept that connects the administered dose with the actual initial concentration present in the circulation and it is an important parameter to describe the in vivo distribution for drugs.
• In practical, we can speculate the distribution characters for an unknown compound according to its VD value, such as its condition binding to plasma protein, its distribution amount in body fluid and its uptake amount in tissues.

BCRP Inhibitor

• The breast cancer resistance protein (BCRP) is widely distributed and expressed in many normal tissues, especially the small intestine, liver, brain endothelium, and placenta. It is a vital constituent part of blood–tissue barriers and is closely involved in absorption blocking and excretion enhancing. BCRP inhibitors can enhance the bioavailability of BCRP substrates.

CYP450 Inhibitor / Substrate

• The cytochrome P450 enzymes represent a diverse superfamily of hemoproteins present in eukaryotic, bacterial, and archaean systems. The primary function of these enzymes is in the metabolism and clearance of both endogenous and exogenous (xenobiotic) compounds due to their propensity to metabolize multiple substrates through the catalysis of a range of reactions. They play important roles in drug metabolism and detoxification, especially in oxidative metabolic reactions.

OATP1B1 / OATP1B3 Inhibitor

• Organic anion transport peptides (OATPs) belong to the solute carrier superfamily and mediate the transmembrane transport of drugs and endogenous substances. There is a high expression of OATP1B1 and OATP1B3 in the liver, which is located on the basal side of liver cells and plays a crucial role in the hepatic uptake of drugs. Transporter-mediated uptake rate is a determinant of total drug clearance, as drugs are metabolized intratranically through uptake of OATP1B1 and OATP1B3 to the liver.

OCT2 Inhibitor

• OCT2 is a primarily renal uptake transporter that is expressed on the basolateral (blood) side of proximal tubule cells. It plays a key role in the disposition and renal clearance of mostly cationic drugs and endogenous compounds. It functions in conjunction with MATE1 and MATE2-K which facilitate the elimination of OCT2 substrates into the urine.

PXR Activation

• The human pregnane X receptor (PXR) regulates the expression of several drug metabolizing enzymes and induction of these proteins is a major mechanism for developing drug resistance in cancer.

UGT Activation

• UDP glucuronosyltransferases (UGTs) are a class of important cellular enzymes that participate in the metabolism and detoxification processes of drugs, toxins, endogenous compounds, etc. in organisms. UGTs combine glucuronic acid with metabolites to form a large water-soluble substrate of glucuronic acid, which facilitates the easier excretion of these substrates in the body. UGTs mainly exist in liver cells and are also distributed in other tissues, such as the intestine, kidneys, and lungs. They play an important role in the metabolism of many exogenous and endogenous compounds.

Clearance

• The clearance of a drug. Clearance is an important pharmacokinetic parameter that defines, together with the volume of distribution, the half-life, and thus the frequency of dosing of a drug.

Half Life

• Half life of a drug is the duration for the concentration of the drug in the body to be reduced by half. It measures the duration of actions of a drug.

Ames Toxicity

• Mutagenicity by Ames test. Ames test, also known as bacterial reverting mutation test, is a required test item in the international general genotoxicological evaluation system, and is also one of the tests to verify the results of the development of many emerging technologies in genotoxicology, and is widely used in the preliminary screening test of the mutagenicity and potential carcinogenicity of compounds.

Biodegradation

• Biodegradation is an important process to remove chemicals from water, soil, and sediment environments through oxidation, reduction, and hydrolysis by microbes. Accumulation of not readily biodegradable chemicals can pose threats to human health and ecosystems.
• Compounds with a BOD value greater than 60% were labeled with “1”; otherwise they were regarded as “0”.

BZR Inhibition

• Benzodiazepine receptors are a class of receptor proteins located in the central nervous system. These receptors bind to benzodiazepine drugs (such as diazepam drugs) and regulate neurotransmitters γ-aminobutyric acid (GABA).

Caenorhabditis elegans Toxicity

• Caenorhabditis elegans toxicity assays provide data from a whole animal with intact and metabolically active digestive, reproductive, endocrine, sensory and neuromuscular systems. About 40% of the genes in the nematode genome are homologous to the human genome, so toxicology studies in C. elegans will largely reflect the toxic damage that toxicants may cause to humans.

Carcinogenicity

• Carcinogenicity is one of the most concerned properties of chemicals to human health, thus it is important to identify chemical carcinogenicity as early as possible.
• The carcinogenic potency is expressed as TD50 values. For a given target site, if there are no tumors in control animals, the TD50 value is the chronic dose-rate in mg/kg/day which would induce tumors in half of the test animals at the end of a standard lifespan for the species. The chemicals are labeled as “1” and “0” according to the TD50 values.

ClinTox

• Clinical trial toxicity. The ClinTox dataset contains qualitative data on FDA-approved drugs, as well as drugs that failed in clinical trials for toxic reasons.

COX-2 Inhibition

• Cyclooxygenase-2 (COX-2) is an enzyme that belongs to the lipoxygenase family. It plays an important physiological role in the body, participating in the synthesis process of prostaglandins. Prostaglandins are an important class of bioactive substances that play a regulatory role in physiological and pathological processes such as inflammation, pain, fever, and platelet aggregation.

DDD

• The defined daily dose (DDD) is a statistical measure of drug consumption, defined by the World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology as the assumed average maintenance dose per day for a drug used for its main indication in adults. The DDD enables comparison of drug usage between different drugs in the same group or between different health care environments, or to look at trends in drug utilisation over time.

DILI

• Drug-induced liver injury refers to the direct or indirect liver damage caused by the drug itself or its metabolites to varying degrees during the use of drugs within the normal therapeutic or clinical trial dose range, and is one of the most common serious adverse drug reactions.

ER Affinity / Inhibition

• Estrogen receptor (ER) is a protein receptor located within cells, which has a high affinity for estrogen hormones (mainly estradiol). ER mainly exists in the nucleus of mammalian cells, but can also be found in other subcellular cells. The main role of ER in organisms is to regulate gene expression.

Eye Corrosion / Irritation

• Chemicals can cause loss of vision through corrosivity (corrosion) and irritancy (acute/severe irritation) to the eye.

Fathead Minnow Toxicity

• Fathead Minnow Acute Toxicity is an experimental method for evaluating the toxicity of chemical substances to aquatic organisms, using a small freshwater fish called Fathead Minnow (Pimephales promelas) as the test subject, measuring the concentration of chemical substances that cause 50% mortality (LC50) within 96 hours.

FDAMDD

• The maximum recommended daily dose provides an estimate of the toxic dose threshold of chemicals in humans. Maximum recommended daily dose values were determined from pharmaceutical clinical trials that employed an oral route of exposure and daily treatments, usually for 3-12 months.

Fish Toxicity

• Fish toxicity refers to the nature and degree of toxicity of pesticides dissolved or suspended in water to aquatic animals such as fish and shellfish.

Genotoxicity

• Genotoxicity refers to the potential for an agent to cause DNA lesions that can result in cell death or mutations that can lead to cancer and is an important category in hazard identification studies.

Hepatotoxicity

• Hepatotoxicity of the rat following 28 days of continuous exposure, established by liver histopathology and serum chemistry. A compound was denoted hepatotoxic if it exhibited histopathology characteristics of hepatotoxicity. (Chem. Res. Toxicol. 2011, 24, 8, 1251–1262)

hERG Inhibition

• The human Ether-a-go-go-related gene (hERG) encodes a voltage-dependent ion channel involved in controlling the electrical activity of the heart by mediating the re-polarisation current in the cardiac action potential.
• Malfunction or inhibition of hERG-channel activity by drug molecules can lead to cardiac arrhythmias in the form of prolonged QT intervals and may lead to sudden cardiac arrest.

Honey Bee Toxicity

• The acute toxicity tests with adult honey bees for contact and oral exposure are part of the current requirements for pesticide registration and acute toxicity endpoints are the medial lethal doses (LD50).

IGC50

• Concentration of the test chemical in water in mg/L that causes 50% growth inhibition (IGC50) to Tetrahymena pyriformis after 48 hours.

LC50DM

• Concentration of the test chemical in water in mg/L that causes 50% of Daphnia magna to die (LC50) after 48 hours.

LC50FM

• Concentration of the chemical in the water tested that killed 50% (LC50) of the fathead minnow after 96 hours in an animal acute toxicity test.

LD50

• The median lethal dose (LD50) is a term used in toxicology as a measurement of a lethal dose of a substance. Specifically, the LD50 represents the dose at which a substance is lethal for 50% of tested subjects. A substance with a high LD50 would have a low toxicity, while a substance with a low LD50 would have a high toxicity.

LogBCF

• The biological enrichment factor (BCF) is the ratio of the concentration of an element or compound in an organism to its concentration in the environment. This is an important indicator of the tendency of a chemical substance to accumulate in an organism.

LogHD50

• Hemolytic Dose 50% (HD50) is the concentration of causing 50% hemolysis of red blood cells. HD50 is usually used to measure hemolytic toxicity quantitatively.

NR-AhR

• The Aryl hydrocarbon Receptor (AhR), a member of the family of basic helix-loop-helix transcription factors, is crucial to adaptive responses to environmental changes. AhR mediates cellular responses to environmental pollutants such as aromatic hydrocarbons through induction of phase I and II enzymes but also interacts with other nuclear receptor signaling pathways.

NR-AR

• Androgen receptor (AR), a nuclear hormone receptor, plays a critical role in AR-dependent prostate cancer and other androgen related diseases. Endocrine disrupting chemicals (EDCs) and their interactions with steroid hormone receptors like AR may cause disruption of normal endocrine function as well as interfere with metabolic homeostasis, reproduction, developmental and behavioral functions.

NR-AR-LBD

• Androgen receptor (AR), a nuclear hormone receptor, plays a critical role in AR-dependent prostate cancer and other androgen related diseases. Endocrine disrupting chemicals (EDCs) and their interactions with steroid hormone receptors like AR may cause disruption of normal endocrine function as well as interfere with metabolic homeostasis, reproduction, developmental and behavioral functions.

NR-Aromatase

• Endocrine disrupting chemicals (EDCs) interfere with the biosynthesis and normal functions of steroid hormones including estrogen and androgen in the body. Aromatase catalyzes the conversion of androgen to estrogen and plays a key role in maintaining the androgen and estrogen balance in many of the EDC-sensitive organs.

NR-ER

• Estrogen receptor (ER), a nuclear hormone receptor, plays an important role in development, metabolic homeostasis and reproduction. Endocrine disrupting chemicals (EDCs) and their interactions with steroid hormone receptors like ER causes disruption of normal endocrine function. Therefore, it is important to understand the effect of environmental chemicals on the ER signaling pathway.

NR-ER-LBD

• Estrogen receptor (ER), a nuclear hormone receptor, plays an important role in development, metabolic homeostasis and reproduction. Two subtypes of ER, ER-alpha and ER-beta have similar expression patterns with some uniqueness in both types. Endocrine disrupting chemicals (EDCs) and their interactions with steroid hormone receptors like ER causes disruption of normal endocrine function.

NR-PPAR-gamma

• The peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors of the nuclear receptor superfamily with three distinct subtypes namely PPAR alpha, PPAR delta (also called PPAR beta) and PPAR gamma (PPARg). All these subtypes heterodimerize with Retinoid X receptor (RXR) and these heterodimers regulate transcription of various genes. PPAR-gamma receptor (glitazone receptor) is involved in the regulation of glucose and lipid metabolism.

Respiratory Toxicity

• The respiratory system is relevant in toxicology as a target of toxic effects, and also as a major route of absorption of inhaled gases and atmospheric particles. If inhalation and subsequent absorption reach a toxic threshold, inhaled chemicals have the potential to produce lung disease. If the chemical is translocated to other organs, disease can be produced in those organs.

Skin Sensitization

• Skin disease is the most common injury associated with chemicals. When irritant influences into the skin, the living cells react due to cause inflammation or dermatitis. Inflammation consists of four parts including redness, pain, heat, and swelling. Skin toxicity can be detected easily as the reaction is observed immediately.

SR-ARE

• Oxidative stress has been implicated in the pathogenesis of a variety of diseases ranging from cancer to neurodegeneration. The antioxidant response element (ARE) signaling pathway plays an important role in the amelioration of oxidative stress.

SR-ATAD5

• As cancer cells divide rapidly and during every cell division they need to duplicate their genome by DNA replication. The failure to do so results in the cancer cell death. Based on this concept, many chemotherapeutic agents were developed but have limitations such as low efficacy and severe side effects etc. A new cell based assay was developed to find the compounds that effectively block DNA replication either by directly damaging DNA or by inhibiting other cellular mechanisms. Enhanced Level of Genome Instability Gene 1 (ELG1; human ATAD5) protein levels increase in response to various types of DNA damage.

SR-HSE

• Various chemicals, environmental and physiological stress conditions may lead to the activation of heat shock response / unfolded protein response (HSR/UPR). There are three heat shock transcription factors (HSFs) (HSF-1, -2, and -4) mediating transcriptional regulation of the human HSR.

SR-MMP

• Mitochondrial membrane potential (MMP), one of the parameters for mitochondrial function, is generated by mitochondrial electron transport chain that creates an electrochemical gradient by a series of redox reactions. This gradient drives the synthesis of ATP, a crucial molecule for various cellular processes. Measuring MMP in living cells is commonly used to assess the effect of chemicals on mitochondrial function; decreases in MMP can be detected using lipophilic cationic fluorescent dyes.

SR-p53

• p53, a tumor suppressor protein, is activated following cellular insult, including DNA damage and other cellular stresses. The activation of p53 regulates cell fate by inducing DNA repair, cell cycle arrest, apoptosis, or cellular senescence. The activation of p53, therefore, is a good indicator of DNA damage and other cellular stresses.

TD50

• Half toxic dose (TD50) is the dose that causes 50% toxicity (usually cancer) in an animal tested for toxicity in the event of prolonged and continuous exposure to a substance. It is often used to assess the chronic toxicity of a substance.

Tetrahymena pyriformis Toxicity

• Tetrahymena pyriformis is a unicellular animal with typical eukaryotic organelles. Its metabolic function is very similar to the function of the kidney and liver in mammals, and has some metabolic functions of the overall animal life. It has become a commonly used test animal for the detection and evaluation of toxic substances, nutrients, antibacterial drugs, anticancer drugs and carcinogens.