ADME Properties Leading to Toxicity

Drug Discovery Toxicology From Target Assessment to Translational Biomarkers, First Edition. Edited by Yvonne Will, J. Eric McDuffie, Antkew J. Olaharski, and Brandon D. Jeffy. 

---

The partition coefficient and aqueous solubility are properties important for the study of the adsorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of drugs. The prediction of the ADME-Tox properties of drug candidates has recently attracted much interest because these properties account for the failure of about 60 % of all drug candidates in the clinical phases. The prediction of these properties in an early phase of the drug development process could therefore lead to significant savings in research and development costs. 

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. 

Pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. Hence, physicochemical as well as ADMET properties need to be fine-tuned even in the lead optimization phase. Recently developed in silica approaches will further increase model predictivity in this area to improve compound design and to focus on the most promising compounds only. A recent overview on ADME in silica models is given in Ref [128]. 

An integrated approach to the use of ADME studies in conjunction with extensive toxicity testing of PBO has been crucial for the development of an optimal regulatory position for the compound. The toxieokinetic studies explain how PBO is metabolized by the body, and how this process in turn leads to its efficacy as synergist for insecticides and also to its activity as a mixed function oxidase inducer in mammals. The latter property accounts for the principal toxicological hndings seen with the compound, namely liver tumours in mice and weak thyroid effects in rats. 

Lead generation offers an opportunity to initiate the drug discovery process with the best possible chemical starting points. In this phase, a project can survey a wide diversity of compoimds to identify novel compounds that balance potency with appropriate physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties and a low risk of toxicity. Later in the optimization process, when locked in to a small number of series, it may be much more difficult to improve one property without having a negative effect on another. 

Medicinal chemists always followed and still apply the principle of chemical and biological similarity. Whenever they discover an active lead, they modify its chemical structure more or less systematically, to find similar analogs with improved activities, selectivities, ADME (absorption, distribution, metabolism, elimination) properties fewer side effects and less toxic properties. However, as discussed above, structurally closely related analogs may have significantly different specificity or even a completely different mode of action. 

---