ADME properties, of drugs

Yamashita F, Hashida M (2004) In silico approaches for predicting ADME properties of drugs. Drug Metab Pharmacokinet 19, 327-338. 

This edition incorporates a new trend in drug discovery namely the consideration of pharmacokinetics and ADME properties of drugs (absorption, distribution, metabolism, excretion) early in the process. As prospective new drugs are tested in more complex systems (with... 

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. 

To meet the need of conducting HTS for ADME-Tox properties, many slow and expensive in vivo ADME assays are now being replaced by in vitro cell models. For intestinal absorption, Caco-2 cell lines and Madin Darby canine kidney (MDCK) cell lines are widely used to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. A number of models for Caco-2 cell permeability and MDCK cell permeability have been reported that predict the oral absorption properties of drugs, mostly limited to small organic molecules. Caco-2 and MDCK permeability are related to "A" and "D" in the ADME-Tox. 

Castillo-Garit, J.A., Marrero-Ponce, Y., Torrens, F., Garcia-Domenech, R. Estimation of ADME properties in drug discovery predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices. J. Pharm. Sci. 2008, 97, 1946-76. 

It is theoretically possible to simulate all the parameters which determine the ADME properties of a drug in humans. Indeed, this has already been put into practice successfully for many of these parameters. However, at the current time, such simulations are still in the early stages of development and they are rarely put to their full use by incorporation into CTS. Moreover, the focus of such extrapolations has been to obtain values in the average man rather than investigating the possible range of parameters expected in a large population of virtual individuals. 

Pharmacokinetic interactions are adverse effects that occur due to altered body burden of a drug as a result of a coadministered drug that can occur because of the ability of one drug to alter the absorption, distribution, metabolism, and excretion (ADME properties) of the coadministered drug. Of the ADME properties, drug metabolism represents the most important and prevalent mechanism for pharmacokinetic interactions. 

An increased use of models predicting oral absorption will not only reduce the ADME-related attrition in the clinic but also increase the speed of the discovery process. Even though the models can give a good estimate of the ADME properties of molecules, it is most likely that the in sttico models of the future will be used in concert with in vitro and in vivo models to predict the complex ADME profile of compounds that have advanced to a later phase in the drug discovery process. 

It is worth considering the actual mechanics of clinical pharmacokinetics to get an idea of what data actually drives the conclusions around determining ADME properties of drags. A basic and important process is the measurement of the concentration of drug in the bloodstream at various times after administration. The elimination of... 

Importantly, the structural differences within the linker and surface recognition portion will have profound effects on subtype selectivity and physicochemical/ ADME properties of the compounds. Structural changes within these areas will hence allow for optimization and fine-tuning of the drug-like parameters that are required for a successful therapy. 

---