Research Projects

1. Aspect of biotransformation enzymes gene regulation-implication for pharmacotherapy and prediction drug-drug-interactions

Nuclear receptors (NRs) such as Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and Aryl Hydrocarbon Receptor (AHR) are the most important ligand/xenobiotic-activated transcription factors responsible for both basal and inducible expression of genes involved in drug metabolism and detoxification. However, only little is known about regulation of cytochrome P450 enzymes and drug transporter by cellular signaling and about so called crosstalk of transcription factors/nuclear receptors with nuclear receptors for endogenous hormones. The aim of the research line is to examine the effects of selected hormonal receptors and signaling pathways on activity of PXR and CAR in the hepatic and intestinal regulation of gene expression and to examine the effect of hormones on AHR-mediated expression of CYP1 family genes. The project could describe novel mechanistic aspects of drug/xenobiotic-metabolizing enzymes regulation in human hepatocytes, temporal effects of nuclear receptors based on mathematical modelling and have important clinical implication for personalized pharmacotherapy.

The project is conducted in collaboration with Prof. Dvorak´s research group, Department of Cell Biology and Genetics, Palacky University in Olomouc.

2. Clinical pharmacy and pharmacogenetics

The aim of this project is to apply pharmacogenetics in personalized pharmacotherapy of patients suffering from rheumatoid arthritis. We mainly focus on the influence of polymorphisms in genes involved in folate and adenosine pathways and involved in pharmacokinetics of methotrexate.

The project is conducted in collaboration with Dr. Tomas Soukup, Faculty Hospital in Hradec Kralove and with Prof. Jiri Vlcek, Department of Clinical and Social Pharmacy.

3. Research of drug-dietary supplements interactions and nutrigenetics

Dietary supplements containing natural compounds are increasingly popular. Dietary supplements became an alternative to classical medication and they are widely believed to be safe and without any adverse effects or interactions with drugs. However, some natural compounds present in high concentrations in dietary supplements are known to cause serious toxicities. Moreover, the toxicological profiles of certain supplements have not been systematically examined. The aim of the project is to evaluate interactions of selected natural constituents with drug-metabolizing enzymes, transporters and nuclear receptors to predict possible interactions with clinically relevant drugs and further characterize biological properties of the natural compounds and their metabolites. The influence of genetic predisposition on kinetics and adverse effects of these compounds will also be followed.

The project is conducted in collaboration with consortium of the Centre of drug-dietary supplements interactions and nutrigenetics (CDDIN).

4. Novel cellular models for drug development

Primary human hepatocytes are recommended in the different stages of drug development. Limited availability of high-quality human hepatocytes, the interindividual variability in biotransformation enzymes activities, and the decrease in liver-specific functions in culture are serious limitations of the model. Therefore the aim of the project is to generate genetically-engineered cellular models or cellular models based on iPSC stem cells for drug development and for high-throughput testing. At the same time, we are working on validation, application and development ADMET assays for drug research and development. Finally, we working on searching of novel ligands of several targets molecules and we are involved in development of new anti-TB drugs (in collaboration with Prof. Hrabalek´s research group).

 

Last update: 5/3/2016

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