ADME profiles

Wan, H., Ulander, J. High-throughput pKa screening and prediction amenable for ADME profiling. Expert Opin. Drug Metah. Toxicol. 2006, 2,139-155. 

Included in this table are criteria related to kinase inhibition, including detailed analyses of reversibility, detergent effects, and competition with ATP. Also listed are criteria for selectivity, cellular activity, and the physicochemical and in vitro ADME profiles. The final two criteria require the lead to be part of a series of compounds with demonstrated SAR. 

In silico ADME profiling of compound libraries in early discovery has become a valuable addition to the research toolbox of computational and medicinal chemists. A computational alert was developed by Lipinski based on the physico-chemical... 

In vitro ADME profile assay selection and profile... 

Using pharmacological profiles one may be able to predict therapeutic area or ADRs. Using the ADME profile the user may be able to predict the intestinal permeability, metabolic stability, and drug/drug interactions. 

Identification of compounds with similar ADME profiles using clustering... 

Neighbor-based ADME interpretation can also be performed using the in vitro ADME subset of the BioPrint profile. Just as the pharmacological profile of a new compound is used to look for compounds with similar pharmacological profiles, the ADME profile can be used to identify compounds with similar ADME profiles. 

Here too, Pearson clustering with complete linkage can be applied to identify compounds with similar ADME profiles. Having identified BioPrint drugs with similar ADME profiles, the BioPrint pharmacokinetics database (which contains literature pharmacokinetic data on over 1000 drugs) is queried and predictions for the test compound are made based on the pharmacokinetic profile of the ADME nearest neighbors. 

Figure 8. Heat map of a cluster of BioPrint compounds with similar in vitro ADME profiles. Eight ADME assays are clustered on the X-axis and 8 compounds are clustered on the Y-axis. Normalized data range from 0 (blue-green) to 2 (red). Clustering is performed using Pearson correlation and complete linkage using normalized dataset. Where available in literature, human in vivo oral absorption (oa) and oral bioavailability (ba) values (%) are presented after the compound name.

Figure 8 shows a cluster of BioPrint compounds with similar ADME profiles. All the compounds in this cluster share the pharmacokinetic properties of having near total oral absorption and oral bioavailability. Thus, we have identified an in vitro ADME profile that appears to be highly predictive of good absorption and bioavailability properties. 

Bioprint (Cerep) Drug-focused pharmacology/ADME profiling database, full matrix 2400 Experimentally determined data, full data matrix Yes... 

In terms of ADME profiles, do subsets of the target population behave differently from the general population ... 

In addition this method of the bile fistula rat can be used for ADME profiling of drug candidates with respect to a hepatobiliary elimination potential (high first pass effect) (Herling et al. 2002). 

Klein C, Kaiser D, Kopp S, Chiba P, Ecker GF. Similarity based SAR (SIBAR) as tool for early ADME profiling. / Comput Aided Mol Des 2002 16 785-93. 

Figure 19.2 Schematic view of the ADME profiling process in drug discovery and stages of preclinical evaluation prior to going into first human trials (note that the results of in vitro and in vivo toxicity assays are used to refine in silico models).

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. 

Wu X, Wang J, Tan L et al (2012) In vitro ADME profiling using high-throughput rapid-fire mass spectrometry cytochrome p450 inhibition and metabolic stability assays. J Biomol Screen 17 761-772... 

A recent survey [84,85] shows that failures in clinical testing of new molecular entities can be attributed to issues related to the absorption, distribution, metabolism, and excretion (ADME) of compounds. Researchers are nowadays quite aware of the fact that poor ADME properties are at least as unwanted as lack of efficacy or selectivity. Therefore it is desirable to identify indicators that link the chemical and ADME property space these indicators can guide the synthesis of potent compounds with improved ADME profiles. As mentioned before, one of the first attempts to correlate... 

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