ADMET properties, Absorption

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Early determination of PK properties (absorption, distribution, metabolism, excretion and toxicity, ADMET) has become a fundamental resource of medicinal chemistry in the LO phase. New technologies have been developed to perform a great number of in vitro and even in silico tests. Currently, the most common early-ADME assays evaluate both physicochemical properties (such as the solubility in an opportune medium, the lipophilicity, and the p K i) and biophysical properties (such as the permeability through cellular monolayers to predict oral absorption and the metabolic stability after treatment with liver or microsomal subcellular fraction that contains oxidative cytochromes). 

In vitro cell-based models have been developed to aid in the evaluation of ADMET properties of compounds to explore the influences of species differences. CaCo-2 cells, for example, constitute an immortalized line of heterogeneous human epithelial colorectal adenocarcinoma cells widely used to predict the absorption rates of candidate drug compounds across the intestinal epithelial cell barrier. Drug absorption rates are determined 21 days after CaCo-2 cell seeding to allow for monolayer formation and cell differentiation. 

Other HTS assay advances include the us-e of microorganisms such as bacteria and yeast, the cloning and expression of mammalian receptors in microorganisms, probing protein-protein inlcraclions. and veiy importantly. DNA and protein arrays. These are loo involved to discuss here, but excellent reviews exi.sl.- - The increasing use of HTS to screen fora molecule s absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties has been covered as well. ... 

Figure 17.1 Correlation of rank order for ADMET Risk and human intestinal absorption (H IA%). The ADMET Risk score ranged from 0 to 5, with 5 being compounds with the greatest risk of having poor ADMET properties. Within a single ADMET Risk number, the compounds were ranked according to ascending estimated human jejunal permeability (ADMET Predictor, Simulations Plus, Inc.). Spearman rank correlation coefficient was 0.7 (pcO.OOl).

Overall, PBPK models can provide insight into the several aspects associated with the kinetics of a drug within the human body, collectively termed as ADMET, for absorption, distribution, metabohsm, elimination, and toxicity. An application of the PBPK models at the early stage of drug development can be useful to rapidly screen candidate drugs based on their PK properties via in silico approaches (3,4). Due to the rapid increases in the computational power, and the parallel advances in the PBPK area, the role of PBPK models in pharmacometrics is likely to substantially increase. 

This chapter describes some of the approaches and techniques used currently to derive in silico models for the prediction of absorption, distribution, metabolism, elimination/excretion, and toxicity (ADMET) properties. The chapter also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intention of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development. 

Absorption, distribution, metabolism, excretion, and toxicology (ADMET) properties determine the pharmacokinetic and safety behavior of compounds and thus to a large part, how effective a compound acts as a drug, how the compound has to be dosed, and what safety window has to be considered. Due to the decisive role of ADMET properties in lead optimization and drug development, these parameters are investigated very early by in vitro systems. For example, Caco-2 cell lines are used to estimate permeability of compounds, while liver microsomes are used to study metabolic stability of novel compounds in vitro [1,2]. 

Prediction of absorption, distribution, metabolism and excretion/toxicity (ADMET) properties. To deveiop its pharmacoiogical activity, a drug candidate has to penetrate various physioiogical barriers, move to its effector site, be modified by specialised enzymes and finally be removed from the body. In other words, it requires some particular properties of absorption, distribution, metabolism and excretion without being toxic. ADMET properties have been identified... 

The attraction of lipophilicity in medicinal chemistry is mainly due to Corwin Hansch s work and thus it is traditionally related to pharmacodynamic processes. However, following the evolution of the drug discovery process, lipophilicity is today one of the most relevant properties also in absorption, distribuhon, metabolism, excretion and toxicity (ADMET) prediction, and thus in drug profiling (details are given in Chapter 2). 

A number of recent success stories prove that DOS compounds provide invaluable tools for target validation — see Panel B of Fig. 4. The validation of the ADMET (absorption, distribution, metabolism, excretion, and toxicology) and in vivo properties of these compounds and their value as... 

---