Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods.
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.
Johns Hopkins Bloomberg School of Public Health, Center for Alternatives to Animal Testing (CAAT), Baltimore, USA.
Katya
K
Tsaioun
Institute for Risk Assessment Sciences, Division of Toxicology, Utrecht University, Utrecht, The Netherlands.
Bas J
BJ
Blaauboer
Johns Hopkins Bloomberg School of Public Health, Center for Alternatives to Animal Testing (CAAT), Baltimore, USA.|University of Konstanz, CAAT-Europe, Konstanz, Germany.
Thomas
T
Hartung
D000826:Animal Testing Alternatives / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008657:Metabolic Clearance Rate / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D013678:Technology, Pharmaceutical; D018675:Toxicity Tests / Q000379:methods*
D004364:Pharmaceutical Preparations
ADME; evidence-based toxicology; pharmacokinetics (PK); physiologically-based pharmacokinetic (PBPK) model; systems toxicology