Absorption, distribution, metabolism, and excretion ADME properties

From a DMPK perspective, a common goal is to be able to compare multiple compounds based on their absorption, distribution, metabolism and excretion (ADME) properties as well their preclinical PK properties [8, 12-22]. Therefore, lead optimization typically is performed as an iterative process that uses the DMPK data to select structural modifications that are then tested to see whether the DMPK properties of the series have been improved. This iterative process is shown schematically in Fig. 13.2. Clearly an important element for the successful lead optimization of a series of NCEs is the ability to perform the DMPK assays in a higher throughput manner. The focus of this chapter will be to discuss ways that mass spectrometry (MS), particularly HPLC-MS/MS can be used to support the early PK studies for NCEs in a higher throughput manner. 

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. 

This cough model was used to determine SARs ofNTI derivatives. In addition to the antitussive efficacy of compounds, it is possible to assess not only compounds intrinsic affinity for the receptor but their absorption, distribution, metabolism, and excretion (ADME) properties. 

Klon, A.E., Lowrie, J.F. and Diller, D.J. (2006) Improved naive Bayesian modeling of numerical data for absorption, distribution, metabolism and excretion (ADME) property prediction. Journal of Chemical Information and Modeling, 46, 1945-1956. 

How can late-stage clinical attrition be reduced and yet still produce a safe and efficacious drug This is the number one question that every member of the biophar-maceutical industry is trying to answer. Reducing early-stage clinical attrition is a difficult task because animal models are not perfect predictors of efficacy and safety in humans [8], Many factors can confound the safety and efficacy predictions used to move a new chemical entity (NCE) into the clinic, among them absorption, distribution, metabolism, and excretion (ADME) properties and the mechanism of toxicity differences between the preclinical species and humans. 

Several review articles in recent years have described the role that a drug metabolism and pharmacokinetics (DMPK) department can play in the process of new drug discovery [1, 2, 4-11]. As shown in Figure 1, DMPK provides the tools and the assays to assess various new chemical entities (NCEs) in terms of their absorption, distribution, metabolism and excretion (ADME) properties as well as their pharmacokinetic (PK) parameters. In addition, DMPK scientists may also use various screens to understand the potential of NCEs for preclinical or clinical toxicity [12]. The goal of these efforts is to find a compound that is suitable for development. 

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