Foreword
-
Published:20 Nov 2015
-
Special Collection: 2015 ebook collectionSeries: Drug Discovery Series
New Horizons in Predictive Drug Metabolism and Pharmacokinetics, ed. A. G. E. Wilson, The Royal Society of Chemistry, 2015, pp. P007-P008.
Download citation file:
It is a measure of the maturity of a branch of science as to how successfully it is able to predict the phenomena with which it deals. The development of a science proceeds in a series of steps; firstly, the observation and description of phenomena, then the development of an understanding of the origin of these phenomena and finally the emergence of a theoretical basis for the phenomena, which in turn provides a basis for a priori prediction. Experience across a wide range of sciences shows that this growth in the extent and depth of knowledge relies upon the interaction of experimental and theoretical approaches. The development of drug metabolism and pharmacokinetics, which depends upon progress in a group of chemical and biological sciences, illustrates this sequence very well.
The first experiments to elucidate the fate of foreign compounds in living organisms in the nineteenth century led to the description of the vast majority of the metabolic pathways for foreign compounds along with the recognition of the routes for their elimination. Although it was assumed that these pathways were mediated by enzymes, the basis for this did not emerge until the 1950s. Later, from the 1970s onwards, it became clear that these enzymes are not single entities but exist in families of closely related proteins. From the 1990s, the very rapid growth of knowledge in molecular genetics facilitated huge developments, providing a mechanistic basis to understand the myriad of genetic and environmental factors that had been observed to influence the disposition of foreign compounds.
Efforts to describe the physiological disposition of xenobiotics lagged somewhat behind. In the 1950s, it was shown that passage across membranes, the basis of absorption, distribution and excretion, was principally a passive process, in which unionized molecules passed through lipid-rich membranes, while ionized molecules did not. These models were refined by the inclusion of other physicochemical properties of drugs, notably lipid solubility, as well as both intra- and extracellular protein binding. However, it was evident that this framework did not describe the behaviour of all molecules and a fuller understanding emerged from the discovery of families of membrane transporter systems responsible for the import and export of xenobiotics from cells.
The mathematical modelling of drug disposition has a long history. The first attempts to describe blood levels of drugs led to compartmental models providing important insights into drug disposition. However, these models had no anatomical basis and could not be easily related to the chemical and biological aspects of drug metabolism mentioned above. The application of engineering principles refined these models, giving them more biological relevance in the form of pharmacokinetic–pharmacodynamic models linking drug disposition to drug effect.
Alongside progress in our ability to describe and understand biological systems, we have seen comparable advances in chemistry, particularly in computational chemistry. These allow the visualisation of the molecular structure and relevant physicochemical properties of both small molecule substrates, and the enzyme and transporter macromolecules with which they have key interactions. Insights into the molecular mechanisms of the function of these enzymes and transporters provide further foundations for predictive drug metabolism and disposition.
It is relatively rare to find that the fate of a drug in the body is dominated by a single mechanism; in general, the problem is describing the complex and subtle interactions between a very large number of processes, some passive, and many mediated by enzymes and transporters. The ability to handle very large datasets and the emergence of new paradigms in systems biology has transformed our ability to describe and predict biological systems, integrating reductionist and holistic approaches. The goal of achieving the a priori prediction of the metabolism and pharmacokinetics of a new drug thus becomes a feasible ambition.
This timely volume represents an authoritative summary of recent progress in relevant fields and the opportunities that exist for further developments from an international group of experts in predictive drug metabolism and pharmacokinetics, many of whom have made major contributions to the subject. I commend the initiative of the editor and publisher in bringing this volume together as well as the efforts of the contributors in producing a book that will be a point of reference for many scientists in academia, and the pharmaceutical and other industries where an understanding of the fate of drugs and xenobiotics is critical, as well as for regulators charged with making key decisions on the use of such compounds. This is a very rich volume that will provide the specialist and general reader alike with an immense amount of interest.
John Caldwell,
Emeritus Professor
University of Liverpool, United Kingdom