Abstract
ADME (absorption, distribution, metabolism, elimination) has rapidly evolved over the past two decades, creating a unique interdisciplinary interface between medicinal chemists, biologists, formulators, toxicologists, clinicians, and regulators across industries, but has advanced most rapidly in the pharmaceutical industry. The implementation of ADME profiling of drug candidates, in conjunction with biological efficacy and safety optimization, has dramatically reduced pharmacokinetic drug failures in clinical trials and has become a lingua franca between disciplines that are involved in drug development. This article briefly reviews the basics and current state-of-the-art of ADME and the major lessons from the pharmaceutical industry on its efficient use, points out the importance of defining ADME properties leading to toxicity across industries for safety and toxicity prediction of chemicals, and raises the issues of quality, reliability, and reproducibility of tests and inclusion of ADME under the umbrella of evidence-based toxicology. Increasingly, in vitro results are used to inform ADME assessments and computer modeling. The aspects of kinetics of substances in cellular models themselves, however, are still too often neglected. ADME information will play a critical role in establishing quantitative in vitro to in vivo extrapolations (QIVIVE), integrated testing strategies, and systems toxicology approaches.
Highlights
Paracelsus, hailed as the founding father of toxicology, is known for the quote: “All things are poison and nothing is without poison; only the dose makes a thing not a poison.” Today, we have refined this notion: The portion of the dose that interacts with the target in the body – the biologically active internal dose – is critical
We know that this rule has exceptions, i.e., the dose-response relationship does not explain some phenomena in toxicology such as idiosyncratic toxicity, which is frequently driven by individual immune responses
I.e., quantitative in vitro to in vivo extrapolation (QIVIVE), is critically important for predicting in vivo exposures corresponding to active concentrations on a cell and tissue level
Summary
Paracelsus, hailed as the founding father of toxicology, is known for the quote: “All things are poison and nothing is without poison; only the dose makes a thing not a poison.” Today, we have refined this notion: The portion of the dose that interacts with the target in the body – the biologically active internal dose – is critical. While hazard generally is a yes/no attribution of a property, it should be linked to some dose/response-relationship, because the kinetics of a substance are highly dynamic This prompts the need for dynamic modeling of toxicokinetics, which is regularly used to explain adverse events in preclinical regulatory toxicology, but is increasingly used to support predictive toxicology. I.e., quantitative in vitro to in vivo extrapolation (QIVIVE), is critically important for predicting in vivo exposures corresponding to active concentrations on a cell and tissue level (and, for making predictive use of in vitro findings) This information represents the complement to hazard identification and characterization by cellular models in developing a systems toxicology approach. This Food for Thought ... article details the state-of-the-art of ADME in toxicology as well as the challenges and opportunities
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
