It is now widely accepted that while Structure-Activity Relationships (SAR) have an important place in drug discovery and design, in particular to identify ligands with optimum affinities for their receptors, the most effective way to increase the therapeutic index of a new drug candidate intended for a specific application is to complement SAR-based approaches with additional data on its metabolites, its pharmacodynamic and pharmacokinetic properties and toxicological implications. In other words, optimisation of in vitro activity through the employment of SARguided synthesis alone is no assurance of favourable in vivo activity, since the latter is subject to pharmacokinetics and metabolism that determine e.g. the drug bioavailability, duration of action, biotransformation into active/inactive/toxic metabolites, and so on. An earlier survey indicated that some 40% of a sample of ~300 new drug candidates investigated in humans were subsequently withdrawn due to serious shortcomings in their pharmacokinetics, as reflected in e.g. poor oral absorption, extensive first-pass metabolism, unfavourable distribution or clearance, or a combination of these. This emphasises the need for understanding the principal factors affecting pharmacokinetics viz. drug lipophilicity and solubility. These properties can be manipulated by chemical modification of the active compound or via formulation approaches so as to overcome the above problems, ideally without compromising the intrinsic pharmacological activity of the pharmacophore.

From a historical perspective, the rational use of metabolism input to the drug discovery process is a relatively recent innovation [4]. Frequently in the past, such information has mainly been used to explain the failure of a molecule to achieve its expected performance. During the last two decades however, the explosive growth of knowledge in the area of drugmetabolising enzymes coupled with technological advances in analytical instrumentation has allowed medicinal chemists to acquire valuable information on the metabolic fates of new drug candidates at an early stage of their development. In addition, based on a wealth of accumulated data, rules exist for predicting both the pharmacokinetic behaviour of a compound as well as its likely major routes of metabolism from knowledge of its molecular structure and physicochemical properties. During the last decade, there has been a growing emphasis on rapid metabolism assessment in the discovery phase and numerous in silico tools have been developed to predict the metabolic properties of candidate drugs, e.g. their metabolic stability, likely sites of metabolism and ensuing metabolites, rates of metabolism, drug-drug interactions, clearance and toxicology. The status of such computational models has recently been reviewed. Exploitation of the existing knowledge bases and responsible use of computerised resources can aid the medicinal chemist in optimising drug in vivo activity.

As is evident from earlier chapters, nature has evolved a formidable array of metabolic mechanisms to handle both endogenous and xenobiotic substances in humans. One feature of the metabolism of xenobiotics is the prevalence of oxidative processes, which may not only detoxify them, but also generate toxic, reactive intermediates such as epoxides and radicals. Mention has been made earlier of the possible negative consequences that can ensue from reaction of such intermediates with endogenous macromolecules. Therefore, as regards drug design, one principle that serves.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access