Addressing Pharmacokinetic Problems

These presented examples of quantitative descriptions of protein-ligand interactions remain to be a very promising area to address affinity and the selectivity challenge in the future. Those approaches are collectively seen as interesting for a more integrated lead optimization on a simultaneous consideration of numerous balanced descriptors and models for optimization. 

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One of the major goals of computational chemistry in the field of drug metabolism and pharmacokinetics (DMPK) is the prediction of oral availability. Several computational approaches have been published to predict this important parameter, starting from the molecular structure [1-3]. However, when applied to real case studies, none of these provided totally convincing results and, correspondingly, there is a lack of any general strategy to address this problem. 

The case studies will also consider situations where chemists have addressed the problem of irritancy to the gastrointestinal tract by making appropriate analogues. As a pharmaceutical chemist, because one will be able to relate the medicinal chemistry to the dmg s pharmacokinetics and pharmacodynamics, one will not only be able to understand why a patient needs a particular dmg, but what the best way to administrate it is, what dose and duration of action to expect (and why this is so), and why it elicits its effect. By understanding the medicinal chemistry of dmgs, from a pharmacokinetics perspective, one will be able to explain ... 

Whatever the scope of your investigations into selectivity, it is critical that you address the issue of product complexation in the sample, particularly com-plexation with metals. Complexation problems are by no means universal, but they are more common than generally realized. If you confirm the occurrence of product complexation, it is important to discover and characterize its source. Even though this may not fall strictly within the usual bounds of assay development responsibilities, the potential for the problem to affect purification, formulation, and even pharmacokinetics demands that this potential source of variation be addressed. Seek to eliminate it. If you cannot eliminate it, then reduce it. If you cannot reduce it, then at least try to maintain it within defined limits. 

Fig. 2.1 Lead discovery requires an integrated approach to address a multiple response surface optimization problem properties related to pharmacokinetics, toxicology and pharmacodynamics require optimization for novel chemotypes. The increased difficulty of finding such optima is suggested by darker backgrounds. Modified from [4] with permission.

In this text, the focus of our discussion is on the last issue. To illustrate the problem, we consider the effect of gender on drug pharmacokinetics (see Chapter 3, Chapter 5, Chapter 7, Chapter 10, and Chapter 12) and then address two important gender-related questions the use of medications during pregnancy and the drug treatment of premenstrual dysphoric disorder (see Chapter 14). 

This new textbook, not least because it deals with the pharmacokinetics and pharmacodynamics of drugs and formulations in children of different ages, also provides a timely discussion of pharmacogenomics and addresses the real problem of medication errors in paediatric practice, often caused by the need to manipulate adult dose forms to deliver drugs to very young people. There are many challenges in the formulation of established, new and orphan drugs for use in paediatric... 

Mass Spectrometry in Drug Metabolism and Disposition Basic Principles and Applications addresses each of these areas through a series of chapters authored by eminent scientists well versed in the application of contemporary mass spectrometry techniques to problems in drug metabolism and pharmacokinetics, with an emphasis on issues in drug discovery and development. The reader cannot help but be impressed by the capabilities of the current generation of LC—MS/MS instruments, which provide a combination of sensitivity, specificity, versatility, and speed of analysis that was difficult to envisage only a few years ago, and whieh have transformed the way drug metabolism studies are conducted. One ean only wonder what lies in the years ahead ... 

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