ADME testing

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

Sugano, H. Artifidal membrane technologies to assess transfer and permeation of drugs in drug discovery. In ADME/Tox Approaches, Tests, B.,... 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

The candidate gene approach directly tests the association of selected genes with drug response or ADR. The major sources of candidates which code for receptor, enzyme or ADME targets, are obtained through literature surveys. Most pharma-... 

The advent of automation techniques moved high-throughput ADME screening from individual test tube to multiwell plates. The use of 96- and 384-well plates produced a data explosion and the need to capture, store, and mine data so that it can be used effectively. A database for storing and... 

Before this topic is left behind, it should be noted that statistical significance is by no means the only consideration in interpretation of toxicity test results. If, in our particular case, the pathologist were to inform us that the brain lesion observed was extremely unusual or rare, we should certainly hesitate to dismiss our concerns because of lack of statistical significance. The toxicologist needs equally to understand biological significance, and, in this case, would almost certainly pursue other lines of investigation (perhaps an ADME study to determine if the pesticide reaches the brain, or a toxicity test in other species) to determine whether the effect was truly caused by the chemical. 

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