Current President’s Message
Hiroshi Suzuki, Prof., Ph.D.
The University of Tokyo Hospital
Since it was established in 1985, the Japanese Society for the Study of Xenobiotics (JSSX) has played an important role in the study of drug disposition. As far as drug concentrations in body fluids are concerned, extensive studies have been performed on drug metabolizing enzymes and transporters from a molecular level to human in vivo situations. At the annual meeting of 2010 held in Omiya, its 25th anniversary symposium described the frontiers of drug disposition studies, and the great contribution made by JSSX to our understanding of drug disposition, drug development and the best use of drugs in clinical settings. This clearly demonstrates that one of the main purposes of the JSSX has been successfully achieved, and the researchers who were responsible for establishing this society should be greatly admired and congratulated for their excellent ideas.
So, what can we look forward to regarding the activities of the JSSX in the next 20-50 years? One of the former activities of the JSSX was a “symposium on drug metabolism, efficacy and toxicity.” Although drug disposition analysis has been developed extensively as discussed previously, the achievements of the JSSX in understanding drug efficacy and toxicity may simply not be enough. At the 20th anniversary meeting held on the island of Maui in 2005, Professor Shoji Awazu stated that our final goal is not restricted to understanding drug disposition itself, but we should also focus on the analysis of drug efficacy and toxicity in humans (presentation pdf). In accordance with his statement, the factors which cause the drop out of potential drug candidates during clinical studies have shifted from pharmacokinetic problems to toxicity/safety and efficacy issues in humans (Frank and Hargreaves, Nat Rev Drug Discov 2: 566-580, 2003).
One of the best ways for us to adapt ourselves to overcome new problems may be to apply the concept of physiologically based pharmacokinetic analysis, which has been used for the analysis of drug disposition, to our understanding of drug efficacy and toxicity. Based on physiologically based pharmacodynamic (PB-PD) and toxicodynamic (PB-TD) analyses, we will be able to quantitatively predict drug efficacy and toxicity based on the molecular mechanisms of drug actions. Although we will have to perform research to reveal the molecular mechanisms of drug actions by ourselves, we will be able to show our own characteristics by quantitatively predicting in vivo pharmacological and/or toxicological effects from in vitro results. As Professor Awazu pointed out, it is also important to integrate systems-biological analyses with physiologically based kinetic analyses. These efforts may be necessary in finding excellent biomarkers to predict the drug efficacy and/or toxicity in humans.
Regarding the role of regulation in drug approval, the US Food and Drug Administration (FDA) also focuses on such mechanism-based analysis of drug toxicity during drug development (Abernethy et al., Clin Pharmacol Ther 89: 793-797, 2011). In this manuscript, the authors also emphasized the importance of systems-biological analysis of drug toxicity, which should be considered in the future for the approval of new drugs. Introduction of such analysis, therefore, will need to be one of the future activities of the JSSX.
Such an approach may also be important in determining new drug target molecules. In most cases, the same in vivo phenotype is observed after inhibiting and/or stimulating one of the plural pathways. Detailed whole cellular or whole body PB-PD analysis will enable us to identify the most effective pathway involved in obtaining the desired pharmacological actions among these plural pathways. By means of such human PB-PD analysis, we can also overcome the problems associated with the inter-species differences in drug efficacy and toxicity. Although analysis using gene knock-out mice is important in understanding the mechanism of contracting diseases and in considering the drug targets, many kinds of inter-species differences between mice and humans, such as those in metabolic pathways of endogenous substrates in maintaining the homeostasis of the life of organisms, can only be overcome by the use of PB-PD analysis.
As described previously, understanding the drug efficacy and toxicity in humans based on PB-PD and PB-TD analyses is important not only in expanding our research activities, but also in considering the future activities of JSSX members in the pharmaceutical industry. In the near future, researchers who are familiar with the kinetic analysis of drug actions will become able to help the pharmaceutical companies by overviewing the entire process of drug development, from the selection of pharmacological target molecules, organization and analysis of pre-clinical and clinical studies to postmarketing survey, from a global standpoint. In addition to maintaining and further expanding our activities involving the study of factors affecting drug disposition, we now have to open a new window looking towards our very bright future.