Pharmacogenetics / Pharmacogenomics – Introduction:

While pharmacogenetics describes genetic variations between individuals and their influence on the efficacy and side effects of drugs, pharmacogenomics examines interactions of drugs with the whole genome: changes of gene expression profiles which are caused by drugs are analysed.

The main question is, why patients who suffer from the same disease, react completely different to an identical drug treatment: while some patients respond in the predicted way (responders), others show no response at all (non-responders). A third group of patients experience severe adverse effects under drug treatment which makes the medication process hazardous.

These differences in drug responses are largely caused by genetic polymorphisms, mostly by single nucleotide polymorphisms (SNPs) and combinations of two or more SNPs. It is the aim to discriminate responders and non-responders to certain drugs for example in the scope of clinical studies and to identify individuals at increased risk for adverse drug reactions each based on variations in relevant genes. Hence, pharmacogenetics and pharmacogenomics are contributing to improve drug treatment and to enable and support the development of drugs, which are safer, more targeted and individualized.

Genetic variability is seen both in the area of pharmacokinetics (absorption, distribution, metabolism and excretion, ADME) and in the area of pharmacodynamics (drug effects).
For example genetic variations can influence the activity or have an effect on the expression of the following proteins:

• Drug metabolizing enzymes, DMEs (Phase I enzymes/Cytochrome P450 enzymes, e.g. CYP2D6; Phase II enzymes, e.g. N-acetyl transferases)
• Drug transporters (Solute Carrier (SLC)- and ATP Binding Cassette (ABC)-transporters, e.g. organic cation transporters, OCTs, as members of the SLC family)
• Drug receptors (ligand controlled ion channels or class 1 receptors, e.g. glutamate receptor; G-protein coupled receptors (GPCRs) or class 2 receptors, e.g. ß-receptor; enzymatic receptors, e.g. insulin receptor; receptors regulating gene expression, e.g. steroid hormone receptor)
• G-proteins, e.g. GNAS1 or GNB3

The figure below shows the relevant pathways including the positions of genes which are important for drug response and drug effects:

Example: Cytochrome P-450 enzymes are the key enzymes of phase I metabolism for detoxification of foreign substances. These are primarily liver enzymes which are involved in conversion and degradation of a large number of drugs. Variants in genes coding for these enzymes lead to different types of metabolizers. So-called fast metabolizers show no effect of certain drugs because at normal dosages drugs are degraded too fast. In the group of so-called poor metabolizers, however, it comes to an accumulation up to ten-fold referring to the desirable standard value with the risk of severe side effects. Due to the analysis of these gene variants the correct dosage of a variety of drugs is significantly facilitated, including cardiovascular drugs (e.g. beta blockers) and anti-depressants.

Our services:

In the area of pharmacogenomics / pharmacogenetics Eurofins Medigenomix offers a comprehensive services portfolio (see Pharma Services Portfolio) for the entire drug development process, from preclinical research to clinical phase III trials. For example, we offer different genome-wide screening approaches, such as transcriptome analysis, resequencing and metagenomic analyses based on the "next generation sequencing" technology. Using state-of-the-art technologies like sequencing, TaqMan and mass spectrometry (MALDI), we offer analysis of all relevant genes, including analysis of defined SNPs within these genes or the analysis of the entire gene of interest including all exons, introns and regulatory regions, like promoters, enhancers and 5'-/3'- untranslated regions.

Please contact us to discuss your project or your study in detail: pharmacogenetics@medigenomix.de