ADME studies lead compounds

An integrated approach to the use of ADME studies in conjunction with extensive toxicity testing of PBO has been crucial for the development of an optimal regulatory position for the compound. The toxieokinetic studies explain how PBO is metabolized by the body, and how this process in turn leads to its efficacy as synergist for insecticides and also to its activity as a mixed function oxidase inducer in mammals. The latter property accounts for the principal toxicological hndings seen with the compound, namely liver tumours in mice and weak thyroid effects in rats. 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

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. 

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

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