FWF P 35312:
Title: Towards Personalised Medicine: use of volatile metabolites (PREDICT)
(March 2022 – February 2025)
Wider research context: Patient-specific toxic side effects and lack of efficacy often hamper the therapeutic benefit of drugs. The reason for this lies in the fact the degradation of drugs by so called enzymes works with varying efficiency in different individuals. The Cytochrom P450 (CYP) enzymes belong to the major enzyme families responsible for drug metabolism in the liver. The use of specific substrates as predictors of drug response would significantly advance this field, the benefits of which would be enormous. A test could assess a patient’s ability to metabolize a drug, leading to improved patient care through the prescription of suitable drugs that are administered at the correct dosage.
Objectives: We will test different substrates with a key CYP enzyme, CYP3A4, for the production and use of unique volatile substrate to provide a measure of its activity. Volatiles that are not normally present in exhaled breath will permit the development of a strategy that would lead to considerable reductions in the dose of a substrate needed for the clinical implementation of a breath test, toxic side-effects and medical costs.
Approach: We will employ an interdisciplinary research programme to involve molecular modeling for substrate selection and engineering, and the use of cell-cultures for in vitro testing and metabolic analyses. The selectivity and specificity of substrates will be tested in two liver-like cell-based systems. These will confirm the suitability of substrates, and guide what modifications are required to optimize kinetic parameters, rate of metabolism and volatility. State-of-the-art, high resolution analytical techniques (gas-chromatography mass spectrometry and proton transfer reaction time of flight mass spectrometry, ultra-high pressure liquid chromatography mass spectrometry) will be employed to facilitate the identification, quantification and monitoring of volatile and non-volatile metabolites.
Innovation: The identification of unique biomarkers resulting from CYP3A4 metabolism provides the underpinning knowledge to develop non-invasive breath tests that can assess an individual’s response to a drug. These tests can be used to assess the best therapeutic outcome at reduced costs. Importantly, the approach we are proposing can be adopted to other CYPs relevant in drug metabolism, e.g. 2D6, 2C9, and 2C19.
Primary researchers involved: University of Innsbruck: Dr. Veronika Ruzsanyi and Prof. Klaus Liedl; Medical University of Innsbruck: Prof. Jakob Troppmair; University of Vienna: Prof. Thierry Langer; Brandenburg University of Technology Cottbus: Dr. Sarah Kammerer.
Contact: Assistant Prof. Dr. Ruzsanyi, F. Lochmann, MSc and V. Stock, MSc (University of Innsbruck)