Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition.

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development.

Predictivity of Simulated ADME AutoQSAR Models over Time.

The automation of model building and model updating (autoQSAR) is an important step forward towards real-time small molecule drug discovery project support using the latest experimental data. We present here a simulation study using real company data of the behaviour of QSAR models over time. Three different global QSAR models, namely, human plasma protein binding, aqueous solubility and log D7.

Improving compound quality through in vitro and in silico physicochemical profiling.

Many compounds entering clinical studies do not survive the numerous hurdles for a good pharmacological lead to a drug on the market. The reasons for attrition have been widely studied which resulted in more early attention to compound quality related to physical chemistry, drug metabolism and pharmacokinetics (DMPK), and toxicology/safety. This paper will briefly review current physicochemical in vitro assays and in silico predictions to support compound and library design through to lead optimization.

QSAR modeling using automatically updating correction libraries: application to a human plasma protein binding model.

It is assumed that compounds occupying the same region of model space will be subject to similar errors in prediction, and hence, where these errors are known, they can be applied to predictions. Thus, any available measured data can be used to refine predictions of query compounds. This study describes the application of a correction library to a human plasma protein binding model.

From in vivo to in vitro/in silico ADME: progress and challenges.

High-throughput screening technologies in biological sciences of large libraries of compounds obtained via combinatorial or parallel chemistry approaches, as well as the application of design rules for drug-likeness, have resulted in more hits to be evaluated with respect to their ADME or drug metabolism and pharmacokinetic properties. The traditional in vivo methods using preclinical species, such as rat, dog or monkey, are no longer sufficient to cope with this demand. This editorial discusses the changes towards medium- to high-throughput in vitro and in silico ADME screening.