People can react very differently to a medication. What helps one person may have no effect on another or be associated with severe side effects. How someone reacts depends, among other things, on their genetic profile, which can be analyzed using so-called pharmacogenetic tests .
Complex enzyme systems are responsible for the metabolism of medicines. They lead to a conversion of the medication, making it easier to excrete from the body. Some drugs are first converted into their active ingredient in the body by enzymes (so-called prodrugs). Variants in the coding genes of these enzymes, e.g. so-called single nucleotide polymorphisms, can lead to reduced or increased enzyme activity and thus influence the metabolism of drugs and therefore their concentration and effect.
In principle, 4 types of enzyme activity (phenotype) are distinguished:
Studies have investigated the relationship between drug concentrations and the likelihood of drug switching in patients patients receiving escitalopram (substrate for CYP2C19) or risperidone or vortioxetine (substrates for CYP2D6). As can be seen, drug switching is more frequent in the extreme phenotypes PM and UM, probably because too high or too low drug concentrations are reached. Higher drug metabolizing capacity in UMs with standard dosing leads to lower drug concentrations and a lower risk of developing an adverse drug reaction (ADR) and vice versa in PMs to lower metabolic capacity, higher concentrations and a higher risk of ADRs. [2]
Almost everyone has one or several genetic variants that affect their drug metabolism. In a study of over 1000 patients, 99% had at least one genetic variant that affects medication [1]. The occurrence of the different genetic variants can vary significantly between different populations.
Currently, more than 20 genes with clinically significant effects on drug metabolism have been identified. The most important of these are CYP2D6, CYP2C9 and CYP2C19 from the cytochrome P450 enzyme family.
[1] Ji, Y. et al. (2016) Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade. The Journal of molecular Diagnostics. 18(3), 438-445., 95(4), 423-432. https://doi.org/10.1016/j.jmoldx.2016.01.003
[2] According to Jukic M, Milosavljević F, Molden E, Ingelman-Sundberg M. Pharmacogenomics in treatment of depression and psychosis: an update. Trends Pharmacol Sci. 2022 Dec;43(12):1055-1069. doi: 10.1016/j.tips.2022.09.011. Epub 2022 Oct 25. PMID: 36307251.
