Abstract
The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity.
Highlights
The goal of this paper, which was presented at the Alzheimer's Drug Discovery Foundation conference in Washington, DC on 3 February 2009 [1] is to briefly review advances in the science of predicting human absorption, distribution, metabolism, excretion and toxicity (ADMET) from in vitro and in vivo models, to review presently available assays as well as those in the process of being validated, and to present a model for designing effective in vitro ADMET programs that are used to advance drug-development programs at the lead-optimization and preclinical candidate selection stages
With the advent of in vitro high-throughput screening, molecular biology and miniaturization technologies in the 1990s, early ADMET assays were developed to predict in vivo animal and human results, at a level of costeffectiveness appropriate for the discovery stage
This produced a major advance in the science of ADMET, and has created a new norm that drug-discovery programs follow in advancing compounds from hit to lead, from lead to advanced lead, and on to nominated clinical candidates
Summary
The goal of this paper, which was presented at the Alzheimer's Drug Discovery Foundation conference in Washington, DC on 3 February 2009 [1] is to briefly review advances in the science of predicting human absorption, distribution, metabolism, excretion and toxicity (ADMET) from in vitro and in vivo models, to review presently available assays as well as those in the process of being validated, and to present a model for designing effective in vitro ADMET programs that are used to advance drug-development programs at the lead-optimization and preclinical candidate selection stages. With the advent of in vitro high-throughput screening, molecular biology and miniaturization technologies in the 1990s, early ADMET assays were developed to predict in vivo animal and human results, at a level of costeffectiveness appropriate for the discovery stage This produced a major advance in the science of ADMET, and has created a new norm that drug-discovery programs follow in advancing compounds from hit to lead, from lead to advanced lead, and on to nominated clinical candidates. ADMET: absorption, distribution, metabolism, excretion and toxicity; BBB: blood-brain barrier; CNS: central nervous system; CYP450: cytochrome P450; FDA: US Food and Drug Administration; IND: Investigational New Drug; MDCK: Madin-Darby canine kidney; MRP: multidrug-resistance protein; NCE: new chemical entity; PAMPA: parallel artificial membrane permeability assay; PET: positron emission tomography; PD: pharmacodynamic; P-gp: P-glycoprotein; PK: pharmacokinetics
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