Drug-drug Interaction and Drug-drug Interaction Evidence Ontology

Gold Book, somewhat modified. It goes on "The process of one material (absorbate) being retained by another (absorbent); this may be the physical solution of a gas, liquid, or solid in a liquid, attachment of molecules of a gas, vapour, liquid, or dissolved substance to a solid surface by physical forces, etc."

A 'cell line cell' is a part of a cell line established through the passaging/selection of a primary cultured cells or the experimental modification of an existing cell line. New types of cell line cells are established after sufficient passaging of a primary culture to establish a stable and homogenous population that qualifies as a line (typically 1-20 passages), or following some spontaneous or experimental modification that confers novel characteristics to an existing line. A cell line cell typically has mutations of five or more genes compared to the original cell that derives the cell line cell. Some gene mutations may turn on some oncogenes. Cell line cells can be in active culture, stored in a quiescent state for future use (e.g. frozen in liquid nitrogen), or applied in experimental procedures.

The term 'line' is used when a culture has undergone an intentional experimental process to establish a more uniform and stable population of cells (see 'establishing cell line'). This will require one or more passages, but may involve additional selection processes. Through such passaging and/or selection processes, the resulting 'line' attains some level of genetic stability and compositional homogeneity which is typically absent in primary cultures. Because of their relative homogeneity, ‘lines’ are capable of being characterized and stably propagated over a period of time. A new type of cell line can be established not only through the passaging/selection of a primary culture, but also through experimental modifications of existing lines (e.g. immortalization, stable genetic modifications, drug selection for a resistant subset, etc.).

The definition provided here establishes the 'scale' of cell populations that qualify as cell lines - specifically those with a shared propagation history in culture. In this way, the 'cell line' class demarcates populations that represent what researchers actually use in the practice of science - e.g. as inputs to culturing, experimentation, and sharing. The definition is such that cell lines will exhibit important attributes. For example, they will have a relatively homogenous cell type composition as they have experienced similar selective pressures due to their continuous co-propagation. In addition, these populations can also be characterized by a passage number, again owing to their common passaging history.  As defined here, 'cell line' can refer to a population of cells in active culture, applied experimentally, or stored in a quiescent state for future use.

disease: colorectal adenocarcinoma

Note that this class was re-labeled to 'cultured cell' instead of 'cell line cell', as it intent was clarified to cover any cultured cells of multicellular and unicellular organisms. This includes cells actively being cultured, or cells that have been cultured but are stored in a quiescent state for future use. In having been cultured, cells must establish homeostasis and often replicate in a foreign environment. Accomodation of this stress initiates a selection of cells fit for such challenges, wherein necessary adaptive biochemical and.or genetic changes can occur. These changes can set them apart from the in vivo cells from which they derive, and such changes will typically accumulate and change over increasing time in culture.

This class has been re-labeled to imply reference only to in vitro experimentally modified cells, similarly, the definition has been slightly updated to reflect this. 'experimentally modified cell' refers only to cells in vitro, and not modified in vivo/in environment cells. There is currently no class representing unmodified in vitro cells (other than the parent 'cell in vitro'), or a class representing modified native cells. More granular subclassing of experimentally modified cell can be found in ReO. MHB 1.12.12

Physiological activity and functions of the gastrointestinal system as a whole or of any of its parts, including digestion, absorption and eliminating waste.

An instance of this entity would represent an optional recommendation for the clinical management of patients who are exposed or about to be exposed to a potential DDI. Management options may be generated by expert opinion, consensus, and/or a review and synthesis of relevant evidence.

An instance of a drug-drug interaction that has been identified in case report or study.

Evidence from a kinetic model that a drug-Y has some effect on the absorption, metabolism and elimination of drug-X.

A drug entity that participate in a drug-drug interaction but for which its role is not assignable as a precipitant or object.

A clinically meaningful alteration in the exposure and/or response to a drug (object drug) that has occurred as a result of the co-administration of another drug (precipitant drug)Oates JA. Chapter 5. Goodman and Gilman 11th ed (2006):117–36; Hines. Response can refer to either precipitating an adverse event or altering the therapeutic effect of the object drug. Although some DDIs may be used for therapeutic benefit, this paper focuses on those with adverse clinical consequences. (based on the 2013 DDI conference series) / has participant some mechanism.

An instance of this occurs when at least two or more drugs are taken in a specific time interval and the individual time interval for each drug administration overlaps with the other drug's or drugs' time interval(s). (SG1)

An instance of this entity would represent the biochemical process by which pharmacokinetic or pharmacodynamic DDI is thought to occur.

An instance of this type represents a information artifact used to establish knowledge for or against the existence of a drug-drug interaction.

Alternative definitions use the risk of harm instead of the risk of an AE.

Term and definition provided by Richard D. Boyce.

Cells isolated from human liver that have been frozen and stored, usually in liquid nitrogen; an in vitro model system for human metabolism or transport; cells can be thawed and used in metabolism or transport assays

Cells isolated from human liver, never frozen; an in vitro model system for human metabolism or transport; cells can be used in metabolism or transport assays

Cells isolated from livers of transgenic animals; an in vitro model system for human metabolism or transport

HepaRG cells are terminally differentiated human hepatocellular carcinoma cells that reproducibly express drug-metabolizing enzymes and transporters. They are commonly used for metabolism and transport evaluations in vitro, as they respond and function like primary human hepatocytes across a range of applications.

Fa2N-4 cell line was prepared by immortalizing hepatocytes from a 12 year-old Caucasian female donor with Simian virus 40 large T antigen. The donor was tested negative for CMV, HIV, HBV, and HCV. This cell line was mainly used for major CYP induction studies (including CYP3A4/5, 1A2, 2B6, and 2C9) with limitations. Hepatic transporter expression levels are low.

An Immortalized human hepatoma cell line possesses the capacities of being reversibly differentiated in vitro, and of maintaining a relatviely higher mtabolic rate in the differentiated phase. It is mainly used for repeated toxicity evaluation in vitro.

Cell cytosol obtained via centrifugation of human liver cells. It is commonly used to support in vitro DMPK studies related to liver cytsolic enzymes, especially non-CYP enzymes, such as phase I enzyme aldehyde oxidase (AO), phase II enzyme SULT.

Cell cytosol obtained via centrifugation of human enterocytes. It is commonly used to support in vitro evaluation of intestinal cytosolic enzymes in the first-pass metabolism of orally ingested xenobitotics.

A mixture of cell cytosol and microsomes isolated by disruption and centrifugation of human liver cells. It contains a wide range of drug-metabolizing enzymes and is commonly used for in vitro DMPK studies, including both phase I and phase II xenobiotic metabolism.

Subcellular fractions, derived from endoplasmic reticulum that has been isolated from enterocytes from a single human donor. They contain a rich variety of metaboliz enzymes for assessing first-pass metabolism for orally ingested drugs.

Subcellular fractions, derived from endoplasmic reticulum that has been isolated from liver cells from multiple human donors. They contain a rich variety of metaboliz enzymes (e.g. CYP, UGT, FMO) for assessing drug DMPK in vitro, such as metabolic stability, CYP inhibition, CYP phenotyping, metabolite charaterization, etc.

Subcellular fractions, derived from endoplasmic reticulum that has been isolated from liver cells from a single human donor. They contain a rich variety of metaboliz enzymes (e.g. CYP, UGT, FMO) for assessing drug DMPK in vitro, such as metabolic stability, CYP inhibition, CYP phenotyping, metabolite charaterization, etc.

Subcellular fractions, derived from endoplasmic reticulum that has been isolated from enterocytes of multiple human donors. They contain a rich variety of metaboliz enzymes for assessing first-pass metabolism for orally ingested drugs.

A mixture of cell cytosol and microsomes isolated by disruption and centrifugation of human enterocytes. It contains a wide range of drug-metabolizing enzymes and is commonly used for in vitro DMPK studies, including both phase I and phase II xenobiotic metabolism.

Insect cell-hosted viral system used to produce and express recombinant proteins/enzymes; these systems are used in metabolism studies

Prokaryotic in vitro system used to produce and express recombinant proteins/enzymes; these systems are used in metabolism studies

Percent inhibition: the percent decrease in activity of a transporter or enzyme in the presence of a compound from activity in the control experiment

Hydroxylation of midazolam at the 1' position to form 1'-hydroxymidazolam;probe substrate of CYP3A4 activity (used to measure CYP3A4 activity)

O-deethylation of 7-Ethoxyresorufin to form resorufin; probe substrate of CYP1A activity

Dehydrogenation of nifedipine to dehydronifedipine;probe substrate of CYP3A4 activity (used to measure CYP3A4 activity)

1'-hydroxylation of bufuralol to form 1'-hydroxybufurolol; probe substrate of CYP2D6 activity

Hydroxylation of omeprazole at the 5 position to form 5-hydroxyomeprazole; probe substrate of CYP2C19 activity

Hydroxylation of bupropion at the 1 position to form 1-hydroxybupropion; probe substrate of CYP2B6 activity

Hydroxylation of paclitaxel at the 6-alpha position to form 6-alpha-hydroxypaclitaxel; probe substrate of CYP2C8 activity

O-deethylation of phenacetin to form acetaminophen; probe substrate of CYP1A2 activity

Hydroxylation of coumarin at the 7 position to form 7-hydroxycoumarin; probe substrate of CYP2A6 activity

Hydroxylation of testosterone at the 6-beta position to form 6-beta-hydroxytestosterone; probe substrate of CYP3A4 activity

O-demethylation of dextromethorphan to form dextrorphan;probe substrate of CYP2C9 activity

Hydroxylation of diclofenac to form 4'-hydroxydiclofenac; probe substrate of CYP2C9 activity

An in vitro system that uses a combination of genetic pieces typically in a plasmid that is incorporated into a host cell which is used to produce the protein of interest

the frequency of administration of the precipitant during the day

HepG2 was derived from a liver hepatocellular carcinoma of a 15 year-old Caucasian male. HepG2 cells secrete a variety of major plasma proteins. They are a suitable in vitro model system for the study of polarized human hepatocytes, with high degree of morphological and functional differentiation in vitro. It can be used for hepatic metabolism, transport, and toxicity evaluations in vitro. It was tested negative for HBV.

Chinese hamster ovary cells transfected with human transporter DNA; an in vitro model used to study transporters

Well characterized immortalized human liver cancer cell line used as an in vitro model system of metabolism or transport

Caco-2 cells treated with siRNA designed to down-regulate specific enzymes or transporters

Immortalized human kideny cells transfected/transduced with a transporter or enzyme; an in vitro model overexpressing transporter or enzyme of interest; used for transporter or metabolism assays

Number of individual liver samples used

Hydroxylation of diclofenac to form 4'-hydroxydiclofenac; probe substrate of CYP2C9 activity

Methyhydroxylation of tolbutamide to form hydroxytolbutamide;probe substrate of CYP2D6 activity

Glucuronidation of estradiol to estradiol-3-glucuronide; probe substrate of UGT1A1 activity (used to measure UGT1A1 activity)

Dog cells transfected with human transporter; an in vitro model used to study transporters

Glucuronidation of lamotrigine; probe substrate of UGT1A4 activity (used to measure UGT1A4 activity)

Hydroxylation of chlorzoxazone at the 6 position to form 6-hydroxychlorzoxazone; probe substrate of CYP2E1 activity

Placeholder for class to be imported from the Reagent Ontology (ReO).

Placeholder for class to be imported from the Reagent Ontology (ReO).

Placeholder for class to be imported from the Reagent Ontology (ReO).

Placeholder for class to be imported from the Reagent Ontology (ReO).

Placeholder for class to be imported from the Reagent Ontology (ReO).

Note that, in addition to forming the root of the molecular function ontology, this term is recommended for use for the annotation of gene products whose molecular function is unknown. Note that when this term is used for annotation, it indicates that no information was available about the molecular function of the gene product annotated as of the date the annotation was made; the evidence code ND, no data, is used to indicate this.

Note that, in addition to forming the root of the cellular component ontology, this term is recommended for use for the annotation of gene products whose cellular component is unknown. Note that when this term is used for annotation, it indicates that no information was available about the cellular component of the gene product annotated as of the date the annotation was made; the evidence code ND, no data, is used to indicate this.

Note that metabolic processes do not include single functions or processes such as protein-protein interactions, protein-nucleic acids, nor receptor-ligand interactions.

Note that an immunoglobulin complex has the function of antigen binding if a suitable antigen is available.