Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Toxicity Testing in Animals01:23

Toxicity Testing in Animals

Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...
Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
Drug Metabolism: Phase I Reactions01:17

Drug Metabolism: Phase I Reactions

A phase I reaction is a biochemical process that introduces a functionally reactive polar group to a substance. This transformation predominantly occurs in the liver, facilitated by the cytochrome P450 system of hemoproteins situated in the lipophilic endoplasmic reticulum of cells. The metabolite generated through this process can have varying polarities. If it is sufficiently polar, it can be easily excreted in the urine due to its water compatibility. However, if the metabolite is nonpolar,...
Drug Metabolism: Phase II Reactions01:14

Drug Metabolism: Phase II Reactions

Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
Bioactivation and Tissue Toxicity01:25

Bioactivation and Tissue Toxicity

Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...
Drug Biotransformation: Overview01:16

Drug Biotransformation: Overview

Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular...

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Patient Preferences for Telemental Health Care in a Federally Qualified Health Center.

Telemedicine journal and e-health : the official journal of the American Telemedicine Association·2024
Same author

Repeat treatment of organotypic airway cultures with ethyl methanesulfonate causes accumulation of somatic cell mutations without expansion of bronchial-carcinoma-specific cancer driver mutations.

Mutation research. Genetic toxicology and environmental mutagenesis·2024
Same author

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

Cancer medicine·2024
Same author

Evaluation of mutagenic susceptibility of different stages in germ cell development of Caenorhabditis elegans using whole genome sequencing.

Archives of toxicology·2023
Same author

Superior mesenteric artery syndrome secondary to thyrotoxicosis.

Journal of surgical case reports·2022
Same author

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications.

International journal of molecular sciences·2021
Same journal

A simple, sensitive microsample LC-MS assay for quercetin and isorhamnetin in mouse and human plasma: application to EMIQ treatment in myotonic dystrophy type 1.

Bioanalysis·2026
Same journal

ADA assays for high-dose biologics: redefining drug tolerance through clinical insights.

Bioanalysis·2026
Same journal

Comparison of SERS spectral data sets of blood serum samples of hypopharyngeal cancer using silver and gold nanoparticles as substrates.

Bioanalysis·2026
Same journal

The Gyrolab platform for immunogenicity assessment and biotherapeutic and biomarker analysis: technical advances and bioanalytical applications.

Bioanalysis·2026
Same journal

Simultaneous quantification of D-penicillamine, D-penicillamine disulfide, and L-cysteine-D-penicillamine disulfide in human plasma: optimization of sample preparation and mass spectrometry procedures to support bioequivalence studies.

Bioanalysis·2026
Same journal

Development and preliminary clinical application of a time-resolved fluoroimmunoassay for anti-rituximab antibodies in membranous nephropathy.

Bioanalysis·2026
See all related articles

Related Experiment Video

Updated: Jun 6, 2026

Multi-step Preparation Technique to Recover Multiple Metabolite Compound Classes for In-depth and Informative Metabolomic Analysis
11:25

Multi-step Preparation Technique to Recover Multiple Metabolite Compound Classes for In-depth and Informative Metabolomic Analysis

Published on: July 11, 2014

Metabolites in safety testing.

Timothy W Robison1, Abigail Jacobs

  • 1US FDA, Center for Drug Evaluation and Research, Office of New Drugs, 10993 New Hampshire Avenue, Silver Spring, MD 20993, USA. timothy.robison@fda.hhs.gov

Bioanalysis
|November 19, 2010
PubMed
Summary
This summary is machine-generated.

Drug safety assessments traditionally focus on parent drug exposure. However, human metabolites not found or disproportionately higher in animal models require safety evaluation per regulatory guidelines.

More Related Videos

Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
10:44

Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures

Published on: March 28, 2017

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
17:28

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation

Published on: June 17, 2015

Related Experiment Videos

Last Updated: Jun 6, 2026

Multi-step Preparation Technique to Recover Multiple Metabolite Compound Classes for In-depth and Informative Metabolomic Analysis
11:25

Multi-step Preparation Technique to Recover Multiple Metabolite Compound Classes for In-depth and Informative Metabolomic Analysis

Published on: July 11, 2014

Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
10:44

Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures

Published on: March 28, 2017

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
17:28

Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation

Published on: June 17, 2015

Area of Science:

  • Pharmacology and Toxicology
  • Drug Development and Regulatory Science

Background:

  • Historically, drug safety assessments relied solely on parent drug concentrations in animal models to gauge systemic exposure.
  • Measuring circulating metabolite concentrations was typically reserved for specialized cases, such as extensively metabolized parent compounds.
  • This approach sufficed when human metabolite profiles mirrored those in preclinical species.

Purpose of the Study:

  • To review regulatory guidances on assessing the safety of human drug metabolites.
  • To discuss industry concerns regarding the Center for Drug Evaluation and Research (CDER) guidance on drug metabolite safety testing.
  • To clarify discrepancies between CDER and International Council for Harmonisation (ICH) guidelines.

Main Methods:

  • Analysis of regulatory guidances, specifically the CDER Guidance for Industry on Safety Testing of Drug Metabolites and ICH M3(R2).
  • Discussion of regulatory review perspectives on nonclinical safety assessment of human drug metabolites.
  • Identification and examination of industry-raised concerns related to metabolite safety evaluations.

Main Results:

  • Human metabolites not detected or present at disproportionately higher concentrations in humans compared to animal test species warrant safety assessment.
  • CDER defines safety-concern metabolites as those exceeding 10% of parent drug systemic exposure at steady state.
  • ICH M3(R2) defines the threshold as 10% of total drug-related exposure, superseding the CDER guidance where differences exist.

Conclusions:

  • Regulatory scrutiny of drug metabolites is crucial, especially when human metabolic profiles differ from preclinical species.
  • The ICH M3(R2) guideline provides the prevailing threshold for evaluating drug metabolite safety.
  • Key industry concerns include extensive parent drug metabolism, intestinal bacterial metabolism, and species-specific metabolite formation.