Current Topics in Medicinal Chemistry - Volume 11, Issue 4, 2011

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The use of in vitro metabolism in scaling to predict human clearance of new chemical entities has become a commonplace activity in the research and development of new drugs. The measurement of in vitro lability in human liver microsomes, a rich source of drug metabolizing cytochrome P450 enzymes, has become a high throughput screen in many research organizations which is a testament to its usefulness in drug desi Read More

This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundame Read More

Quantitative human pharmacokinetic (PK) predictions play a critical role in assessing the quality of potential drug candidates and in selecting a human starting dose for clinical evaluation, where the parameters of clearance, volume of distribution, and bioavailability as well as the plasma concentration time profiles are the desired endpoints. While there are numerous reports validating the use of different methods for pre Read More

ADME prediction is an extremely challenging area as many of the properties we try to predict are a result of multiple physiological processes. In this review we consider how in-silico predictions of ADME processes can be used to help bias medicinal chemistry into more ideal areas of property space, minimizing the number of compounds needed to be synthesized to obtain the required biochemical/physico-chemical profile. Whi Read More

Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or ti Read More

A primary objective of pharmacokinetic-pharmacodynamic (PKPD) reasoning is to identify key in vivo drug and system properties, enabling prediction of the magnitude and time course of drug responses under physiological and pathological conditions in animals and man. Since the pharmacological response generated by a drug is highly dependent on the actual system used to study its action, knowledge about its p Read More

Metabolic activation of new chemical entities to reactive intermediates is routinely monitored in drug discovery and development. Reactive intermediates may bind to cellular macromolecules such as proteins, DNA and may eventually lead to cell death via necrosis, apoptosis or oxidative stress. The evidence that the ultimate outcome of metabolic activation is an adverse drug reaction manifested as in vivo toxicity, is at b Read More

It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. In order to achieve high unbound plasma drug concentration, it seems obvious to design compounds with low plasma protein binding. Similarly to achieve high unbound tissue concentration, we apparently need compounds with low tissue binding. Our theoretical analysis and experimental data demonstra Read More

The gradual alignment with all of drug metabolism with all aspects of drug discovery and development has led to a complete realignment of the way the work is conducted. From a background of conducting bespoke in vivo studies much of the work is now in a high throughput screening mode. Large technological advances have been made, but the nature of drug metabolism processes, being multi-system and promiscuo Read More