GRAZ, AUSTRIA, June 20, 2012 /24-7PressRelease/
-- "For effects and unwanted side effects read the patient information leaflet ..." - every one of us has known this sentence by heart from the days of our early childhood. A key technology for the investigation of effects and unwanted side effects is subject of a research project carried out by the Austrian Centre of Industrial Biotechnology (acib). Together with their industrial partners Novartis and F. Hoffmann LaRoche the acib scientists have developed a technology, which enables to simulate in vitro the metabolization of drugs in the human body - a liver in a test tube, so to speak. The liver is the primary organ for metabolizing pharmaceuticals; the test uses non-Cytochrome-P450 enzymes for the simulation of the metabolic processes in the lab.
It takes years until a new drug comes on the market. Many tests are required to ensure that the drug is not only effective but ideally doesn't produce unwanted side effects, either. To date, pharmaceutical industry needed to predict all possible breakdown products in the body resulting from the use of the drug, produce them chemically and test all of them for their effects. "At the worst all predictions prove wrong because the metabolic processes in the body don't go off as expected," explains Margit Winkler, scientist at the Austrian Centre of Industrial Biotechnology (acib). The new acib method uses endogenous enzymes and in vitro simulates the metabolizing of the drugs in the body.
The pharmaceutical industries keep developing new drug candidates to enhance the treatment possibilities of doctors and thus improve our health. The question is: What happens to pharmaceutical agents in the body? "On the one hand the compounds bring about the desired effects, on the other hand they are degraded so that they can be released more quickly," explains project manager Margit Winkler.
In addition to reductases/dehydrogenases and hydrolases, to date five other oxidative enzyme classes have been known as possibly responsible for the first metabolic step: Cytochrome P450 enzymes (CYPs), flavin monooxygenases (FMOs), monoamine oxidases (MAOs), aldehyde oxidase (AO) and xanthin oxidases (XO). Which of those enzymes in the end degrades a special agent depends on its chemical structure.
During the past years research has mainly concentrated on the CYP family and comparably little attention has been paid to the other four enzyme classes, the so-called non-CYP Metabolising Enzymes (NCMEs). In cooperation with F. Hoffmann LaRoche and Novartis acib has now dedicated itself to these enzymes. "We intend to have available each single enzyme from the human degradation metabolism in order to simulate special functions of the human liver," explains the acib scientist.
With this "artificial liver" the pharmaceutical industries will be able to test new agents and know, at a very early stage, which breakdown products are formed. This information at hand together with an abundance of the right enzymes makes it a child's play to produce sufficient quantities of the degradation products for further investigations - no more guessing!
In the respective research project the acib method was successfully used for the degradation of moclobemide - a monoamine oxidase A (MAO-A) inhibitor known under the brand names Aurorix or Manerix prescribed to patients with depressions. The research project provides the worldwide first possibility to enzymatically produce an exact metabolite in sufficient quantities to make it accessible for further tests. "Novartis and F.Hoffmann LaRoche already use the new Styrian key technology for the development of new agent candidates," states acib CSO Anton Glieder and is pleased that again a new acib technology is being used in drug development. Together with the processes based on enzymes from almond trees and pig liver acib can already look back at a series of new processes for the pharmaceutical industries.
The Austrian Centre of Industrial Biotechnology (acib) is Europe's leading competence centre for industrial biotechnology. It is an alliance of seven Austrian universities and 27 industrial project partners such as BASF, DSM, Sandoz, Boehringer Ingelheim RCV, Jungbunzlauer, F. Hoffmann-LaRoche, Novartis, VTU Technology and Sigma Aldrich. acib is owned by the Universities of Innsbruck and Graz, Graz University of Technology, the University of Natural Resources and Life Sciences Vienna and Joanneum Research.
170 co-workers are actively doing research in more than 30 research projects. The budget amounts to about 60 million Euros until December 31, 2014. Public funding (58% of the budget is provided by the Austrian Research Funding Agency (FFG), the Standortagentur Tirol, the Styrian Business Promotion Agency (SFG) and the Technology Agency of the City of Vienna (ZIT).
The competence centre acib - Austrian Centre of Industrial Biotechnology - is funded in the framework of the Austrian COMET programme (Competence Centers for Excellent Technologies) by the Federal Ministry of Economy, Family and Youth (BMWFJ), the Federal Ministry of Traffic, Innovation and Technology (bmvit) and the provinces af Styria, Vienna and Tyrol. The COMET programme is managed by the Austrian Research Promotion Agency FFG.