european journal of pharmaceutical sciences 36 ( 2 0 0 9 ) 157–170 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ejps Biosimulation of drug metabolism—A yeast based model I. Pieper a,d , K. Wechler b , M. Katzberg b , L. Brusch c , P.G. Sørensen d , F. Mensonides e , M. Bertau a,* a Freiberg University of Mining and Technology, Institute of Technical Chemistry, 09596 Freiberg, Germany b Dresden University of Technology, Institute of Biochemistry, 01062 Dresden, Germany c Dresden University of Technology, Centre of Information Services and High Performance Computing, 01062 Dresden, Germany d University of Copenhagen, Department of Chemistry, H.C. Ørsted Institute, Universitetsparken 5, 2100 Copenhagen Ø, Denmark e University of Heidelberg, Department of Modelling of Biological Processes, Institute for Zoology/BIOQUANT, INF 267, 69120 Heidelberg, Germany article info Article history: Received 4 July 2008 Accepted 8 September 2008 Published on line 8 November 2008 Keywords: Glycolytic oscillation Drug metabolism Biosimulation Saccharomyces cerevisiae Microbial model abstract Computationally predicting the metabolic fates of drugs is a very complex task which is owed not only to the huge and diverse biochemical network in the living cell, but also to the majority of in vivo transformations that occur through the action of hepatocytes and gastro-intestinal micro-flora. Thus, xenobiotics are metabolised by more than a single cell type. However, the prediction of metabolic fates is definitely a problem worth solving since it would allow facilitate the development of drugs in a way less relying on animal testing. As a first step in this direction, PharmBiosim is being developed, a biosimulation tool which is based on substantial data reduction and on attributing metabolic fates of drug molecules to functional groups and substituents. This approach works with yeast as a model organism and is restricted to drugs that are mainly transformed by enzymes of the central metabolism, especially sugar metabolism. The reason for the latter is that the qualitative functioning of the involved biochemistry is very similar in diverse cell types involved in drug metabolism. Further it allows for using glycolytic oscillations as a tool to quantify interactions of a drug with this metabolic pathway. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Before a drug compound is approved for use in humans, extensive studies must be undertaken to establish its effi- cacy and safety. An important factor in the evaluation of the latter is the knowledge of how the drug is metabolised, i.e. how a drug is structurally modified by enzymatic systems. This is important, because secondary or tertiary occurring drug metabolites may display pharmaceutical or toxico- logical action themselves. One particular important aspect ∗ Corresponding author. Current address: Freiberg University of Technology, Institute of Technical Chemistry, Leipziger Straße 29, 09599 Freiberg, Germany. Tel.: +49 3731 39 2384; fax: +49 3731 39 2324. E-mail address: martin.bertau@chemie.tu-freiberg.de (M. Bertau). URL: http://tu-freiberg.de/fakult2/tech/ (M. Bertau). is the high stereoselectivity of enzymatic reactions. How deeply isomers of different stereo-geometry interfere with living systems had been shown by the thalidomide (Conter- gan) tragic in the 1950s. Moreover, in addition to classical metabolism of a drug in the liver, perorally administered pharmaceutically active compounds (PAC) encounter the bio- transformatory activity of the intestinal micro-flora in treated subjects. Therefore, drug action potential is greatly depen- dent on both first pass metabolism and the gastro-intestinal microbial barrier, and the understanding of drug metabolism 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.10.026