| Abstrakt: |
A major cause of morbidity and mortality in contemporary medicine is the outcome of interindividual differences in therapeutic response, drug interactions, and adverse drug reactions. The scope of the problem will only increase because the population ages and grows fatter, the rates of chronic illness rise and the use of multiple medications for extended periods becomes increasingly more common. Negative outcomes to pharmacologic treatment are partly related to genetic and environmental factors influencing pharmacokinetic and pharmacodynamic phases. Interindividual differences in plasma concentrations in patients treated with the same doses if the same drugs have been demonstrated. Variability might also be at the level of receptors, transporters, etc. Despite the growing body of experimental and pharmacological research results, the clinical consequences of genetically inherited differences in drug metabolism are poorly established. Meanwhile, knowledge of pharmacogenetics of receptors and other pharmacodynamic targets is also increasing. The sources of variability in the elimination of a drug are genetic (polymorphisms) and environmental (food intake, drug interactions, etc.). Additionally, the potential influence of physiological factors (gender, age, etc.) and the involvement of homeostatic mechanisms, including endogenous metabolism, must be taken into consideration. Such variability can be manifested interindividually (between individuals) or interethnically (between populations). The evaluation of the relevance for patients of the specific factors requires well-defined clinical studies. The use of phenotyping and genotyping and measurements of drugs and drug metabolites with simultaneous evaluation of response and side effects in prospective studies may give clues to the clinical significance of these effects. Nevertheless, physicians today need to be aware of pharmacogenetic factors, which could influence drug therapy, and should take into account this possibility as a potential cause of undesired effects or therapeutic failure [1]. It would be highly desirable that when a new drug is marketed the knowledge of interindividual and interethnic differences in drug response due to pharmacogenetic factors should be known and considered in order to optimize treatment and improve the cost/benefit ratio [2]. There is a growing consensus on the potential use of pharmacogenetics in clinical practice, and hopes have been expressed for their potential in the development of global health. However, there are two major concerns that may lead to widening the “biotechnological gap” between the developing and the industrialized world: first the unaffordability of some current biotechnological methods for poorer countries, and second the unpredictability of categorizing patients by ethnicity (which is a construct with a substantial social substrate) makes it necessary to analyze multiple described alleles for individual clinical cases. As of today, conventional PCR methodology is available, and automatization using chips is a reality. However, in the near future the development of a variety of methods may decrease the direct cost, so that it will be easier to implement pharmacogenetic analyses as a routine in the clinic [3]. The sequencing and haplotype mapping of the human genome have in the context of increasingly admixtured populations made it feasible and desirable to genotype the most frequent known functional alleles in a given clinical situation [3]. For example, CYP2C9 and CYP2D6 allele frequencies vary between populations and geographical areas, so that in admixtured populations (e.g., in North, Central, and South America) it would be very useful to have genotyping methods that would allow the phenotype of a given patient or healthy volunteer to be predicted. In the present Hot-Topic Issue, two papers deal with this problem (“Ethnic Differences in Pharmacogenetically Relevant Genes”, by R M Engen et al., and “Pharmacogenomics in the Americas: The Impact of Genetic Admixture” by G. Suarez-Kurtz and S. D. J. Pena). An individualized pharmacogenetic approach would allow recommended dosages to be adjusted for each location, considering the growing body of knowledge emerging from pharmacogenetics. Another important aspect to consider as a source of variability is the potential involvement of pharmacogenetic mechanisms in endogenous functioning. Several decades ago, the potential involvement was described of varying allele frequency of one of the most relevant drug metabolizing enzymes, CYP2D6, in psychological factors [4,5]. Since then, although several works have addressed the topic, it remains unclear. In the present issue A. Serretti et al. add another view with potential links to pharmacodynamics in their review “Serotonin transporter gene variants and behaviour”. There have been calls for the use of biotechnologies and pharmacogenetics for global health by improving the drug-treatment of the most important diseases. We cover here the use of pharmacogenetics in relevant clinical problems: psychiatric disorders, by Dorado et al. (“CYP2D6: clinical use during treatment with antipsychotic drugs”) and Chagon et al. (“Susceptibility genes for the side effect of antipsychotics on body weight and obesity”), respiratory diseases by Tantisira et al. (“The pharmacogenetics of asthma therapy”), and infectious diseases by Marques et al. (“Pharmacogenetics and tropical pharmacology”). Considering the rapid growth of knowledge and relevance of critically sensitive issues such as informed consent, and the use and storage of DNA [6], we devoted the last review by Paul et al. to “Ethical aspects of pharmacogenetics”. |
