DARMEC · Drug adverse reactions predictability: exploring the mechanisms underlying the unexplained interindividual differences in drug metabolism and transport

Drug treatment is often inefficient. Only 30–60% of patients respond properly to treatment with e.g. antidepressants, beta-blockers, statins and antipsychotics. Furthermore, adverse drug reactions (ADRs) frequently occur and cause about 7% of all hospital admissions, a frequency that is increased to 30% in elderly subjects above 70 years of age. This is due to a great extent to pharmacokinetics differences.Epigenetic modifications have been demonstrated to potentially participate in the regulation of ~60 human ADME genes. A correlation between the gene’s epigenetic state and possible influence on drug therapy outcome has been experimentally established only in relation to a few ADME genes.Several drugs with epigenetic actions are currently used or on clinical trials. The best examples are DNA Methyltransferases (DNMTs) and Histone Deacetylase (HDACs) inhibitors.In this project, we propose to elucidate the substantial unexplained fraction of interindividual variability in drug response and metabolism using a 3D multi-cell in vitro model of human liver in comparison to transcriptome and phenotype data obtained from a bank of 130 human livers with the following AIMS:AIM1: to unmask the epigenetically regulated ADME genesAIM2: to evaluate the epigenetically regulated ADME genes as interindividual variability biomarkersA list of epimarks of interindividual variation of drug ADME processes will be generated.AIM3: to test the epigenetic influence of candidate drugs. Our objective is to identify the specific ADME genes epigenetically altered by each drug treatment and elucidate the possibilities of interindividual variation in the ADME processes for each of the tested drugs.This approach is extensively multidisciplinary and multisectorial. The experimental design includes tissue bioengineering techniques to develop liver organotypic cultures, drug metabolism functional profiling, and molecular biology approaches, from the perspective of cutting-edge technology.