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ABSTRACT: Individuelle Unterschiede in der Wirkung und Nebenwirkung von Medikamenten sind unter anderem durch individuelle Variationen
in den genetischen Eigenschaften, d.h. durch genetische Polymorphismen, bedingt. Diese erblichen Polymorphismen finden sich
sowohl in Genen, die für Enzyme des Arzneistoffmetabolismus und Arzneistofftransportes kodieren, als auch in Genen für die
unterschiedlichsten direkten und indirekten Zielmoleküle von Medikamenten. Während genetische Varianten von Enzymen des Arzneistoffmetabolismus
und Arzneimitteltransportes indirekt über die Pharmakokinetik (und damit Exposition der Gewebe) Auswirkungen auf die Effektivität
einer Arzneitherapie haben, können Polymorphismen in den Zielmolekülen die Wirkstärke direkt beeinflussen und ein breites
Spektrum an Folgen zeigen, das von einer Unwirksamkeit bis hin zu schweren überdosierungsbedingten Nebenwirkungen reichen
kann. Allerdings ist unser Wissen über Varianten in Zielmolekülen von Medikamenten heute noch weniger fundiert als das über
die Polymorphismen mit Einfluss auf die Pharmakokinetik. Ziel der pharmakogenetischen Diagnostik ist es, anhand molekulargenetischer
Profile die individuelle Arzneimittelwirkung oder das Risiko für Nebenwirkungen besser vorhersagen zu können. Therapieempfehlungen
können insbesondere bei Polymorphismen des Arzneistoffmetabolismus und -transportes in Form von Dosierungsanpassungen gegeben
werden, die zu einem weniger variablen bzw. einem zuverlässigeren Plasmaspiegel und Konzentrationsverlauf von Medikamenten
führen. Derzeit gibt es in Deutschland erst wenige Beispiele für die Anwendung genetischer Tests zur Verbesserung und Individualisierung
der Arzneitherapie in der klinischen Praxis. Die Gründe hierfür sind vielfältig. Zum einen liegen diese im noch wenig verbreiteten
Wissen über die Pharmakogenetik, zum anderen in der noch immer mangelnden schnellen und kostengünstigen Verfügbarkeit der
entsprechenden Labortests. Von großer Bedeutung ist in diesem Zusammenhang aber wohl, dass die meisten Ergebnisse pharmakogenetischer
Forschung bisher nicht in konkrete, therapeutisch verwertbare Schlussfolgerungen und Therapieempfehlungen gemündet sind. Damit
ist in vielen Fällen die Testung auf einen Genotyp noch nicht sinnvoll. Die pharmakogenetische Forschung steht hier häufig
erst an der Schwelle zur klinischen Anwendbarkeit. Für eine Reihe anderer arzneimitteltherapeutischer Maßnahmen, etwa vor
einer Azathioprin-Therapie (Bestimmung der Thiopurin-Methyltransferase-Aktivität), vor einer 5-Fluorouracilbehandlung (Dihydropyrimidindehydrogenase-Diagnostik)
oder vor Therapie mit bestimmten trizyklischen Antidepressiva bzw. Neuroleptika (CYP2D6-Diagnostik) muss man aber heute schon
fragen, ob ihre Durchführung ohne eine vorangehende pharmakogenetische Diagnostik noch zu vertreten ist.
Individual differences in the effect and side effect of drugs are partly due to genetic factors (genetic polymorphisms). The
responsible polymorphisms lie in genes encoding for drug metabolism and transport but also in direct and indirect drug targets.
While genetic variants in pharmacokinetic structures exert effects on drug efficacy via the differences in drug exposure,
polymorphisms in drug targets can directly affect clinical efficacy and may lead to a broad variation spectrum between inefficacy
and severe side effects. However, at present, our knowledge on genetic variants in drug targets is less detailed than the
knowledge on pharmacogenetic variability within drug metabolism. A goal of pharmacogenetic diagnostics implemented in clinical
practice is to better predict the individual drug effects on the basis of molecular-genetic profiles. Therapy recommendations
can be given as dose adjustments, in particular in the case of polymorphisms of drug metabolizing enzymes which will lead
to less variable drug concentrations. At present there are few examples of the application of pharmacogenetic tests in Germany
in order to improve and individualize drug therapy. The reasons for this are multifold. On the one hand it is due to the limited
awareness of pharmacogenetics; on the other hand it may be due to the lack of fast and economical availability of the appropriate
laboratory tests. The most important reason, however, may be that most results of pharmacogenetic research are so far not
translated into therapeutically usable conclusions and therapy recommendations. Thus, testing for a genotype without concrete
consequences for the drug therapy of an individual patient does not make sense. Pharmacogenetic research, thereby, stands
in many cases at the threshold to clinical applicability and in many cases, for instance for the genotyping for thiopurine
methyltransferase polymorphisms prior to azathioprine therapy or of dihydropyrimidine dehydrogenase polymorphisms prior to
treatment with 5-fluorouracil, as well as for diagnostics of CYP2D6 before therapy with certain tricyclic antidepressants
and neuroleptics, one would ask already today whether a such drug therapy is still responsible without pharmacogenetic diagnostics.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 04/2012; 49(10):995-1003. · 0.66 Impact Factor
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ABSTRACT: The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.The Pharmacogenomics Journal advance online publication, 13 December 2011; doi:10.1038/tpj.2011.51.
The Pharmacogenomics Journal 12/2011; · 4.54 Impact Factor
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ABSTRACT: The therapeutic efficacy of oral hypoglycaemic drugs varies between individuals, and pharmacogenetic factors contribute to this variability. The Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) has been shown to play a role in insulin signal transduction and therapeutic failure to sulphonylurea drugs.
We studied the association between the IRS-1 polymorphism and the haemoglobin A1c (HbA1c) level in diabetic patients treated with insulinotropic versus non-insulinotropic hypoglycaemic drugs as a marker for the efficacy of an antidiabetic treatment. Genotyping of the IRS-1 Arg(972) variant was performed in type 2 diabetes patients treated with either sulphonylurea drugs, glinides or insulin or with metformin, acarbose or glitazones using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
Significantly higher HbA1c levels were observed in carriers of the Arg(972) variant after treatment with insulinotropic drugs compared to wild-type carriers (8.3 vs. 7.6%, p = 0.005, independent t-test). Furthermore, patients with secondary failure to insulinotropic hypoglycaemic drugs switching finally to insulin showed even higher HbA1c levels in carriers of Arg(972) compared to wild-type (8.7 vs. 7.6%, p = 0.005, independent t-test).
Thus, we were able to replicate the earlier findings of an association between the IRS-1 Arg(972) variant and secondary failure to sulphonylurea drugs, and further observed a general association between HbA1c and this polymorphism in type 2 diabetes patients treated with insulinotropic hypoglycaemic drugs but not with metformin.
Diabetes Obesity and Metabolism 12/2010; 12(12):1106-12. · 3.38 Impact Factor
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ABSTRACT: The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N=188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N=42 matched extensive metabolizers, N=14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (P=0.03 and 0.003). Effects were also present in the whole (N=188) sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (P=0.05). An exploratory analysis, extended to the whole brain, suggested the involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.
Molecular psychiatry 04/2010; 16(3):237, 333-41. · 15.05 Impact Factor
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ABSTRACT: More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients. The individual drug metabolizing capacity is assessed by genotyping drug metabolizing enzymes. The potential implications of information gained from genotyping are dose adjustments according to genotype. However, even when the consequences of genotype on pharmacokinetics are significant and well known, as in the case of many tricyclic antidepressants and several SSRIs, there is still considerable controversy on whether adjustment of dosage driven by genetic information may improve therapeutic efficacy, and/or adverse events is prevented, to an extent of any practical importance in clinical practice. Different types of pharmacogenetic studies may improve our understanding of the functional consequence of a genetic variant in the clinical setting. The use of intermediate phenotypes instead of broad outcome parameters such as drug response or remission might improve our knowledge on what exactly happens if an individual with a specific genotype takes a certain drug. Here, we review the potential impact of an integrated approach, including the assessment of intermediate phenotypes for the effect of genetic polymorphism, the monitoring of therapy progress, and response prediction in depression.
Current Pharmaceutical Design 12/2009; 16(2):136-144. · 3.87 Impact Factor
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ABSTRACT: The efficacy of a drug therapy is influenced by many different factors such as age, weight, comorbidity and co-medication, which vary between patients, as well as fixed parameters such as gender and pharmacogenetic characteristics. Many enzymes involved in drug metabolism are genetically polymorphic, which means that their activity differs depending on a certain genotype. Drugs will be metabolized slowly in individuals who are carriers of a genetic polymorphism, leading to absent or decreased enzyme activity, and these individuals are at particular risk for adverse drug reactions or therapeutic failure. On the other hand, drug therapy could be ineffective if the drug is metabolized too fast because of a genetic polymorphism. The knowledge of these polymorphisms before beginning a drug therapy could help in choosing the right drug in a safe dosage. In particular, three polymorphic drug metabolizing enzymes are responsible for the metabolism of many commonly used drugs. These enzymes, belonging to the cytochrome P450 (CYP) family, are CYP2D6, CYP2C9 and CYP2C19. Besides beta-blockers and antidepressants, several drugs used in cancer therapy, as well as PPIs, NSAIDs, vitamin K-antagonists and oral antidiabetics are metabolized via these enzymes. Especially for drugs with a narrow therapeutic index and a high risk for the development of adverse drug effects, genotyping could be helpful when choosing the right drug in the optimal dosage for individual patients.
Der Internist 07/2008; 49(7):877-83. · 0.30 Impact Factor
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[show abstract]
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ABSTRACT: Individual differences in the effect and side effect of drugs are partly due to genetic factors (genetic polymorphisms). The responsible polymorphisms lie in genes encoding for drug metabolism and transport but also in direct and indirect drug targets. While genetic variants in pharmacokinetic structures exert effects on drug efficacy via the differences in drug exposure, polymorphisms in drug targets can directly affect clinical efficacy and may lead to a broad variation spectrum between inefficacy and severe side effects. However, at present, our knowledge on genetic variants in drug targets is less detailed than the knowledge on pharmacogenetic variability within drug metabolism. A goal of pharmacogenetic diagnostics implemented in clinical practice is to better predict the individual drug effects on the basis of molecular-genetic profiles. Therapy recommendations can be given as dose adjustments, in particular in the case of polymorphisms of drug metabolizing enzymes which will lead to less variable drug concentrations. At present there are few examples of the application of pharmacogenetic tests in Germany in order to improve and individualize drug therapy. The reasons for this are multifold. On the one hand it is due to the limited awareness of pharmacogenetics; on the other hand it may be due to the lack of fast and economical availability of the appropriate laboratory tests. The most important reason, however, may be that most results of pharmacogenetic research are so far not translated into therapeutically usable conclusions and therapy recommendations. Thus, testing for a genotype without concrete consequences for the drug therapy of an individual patient does not make sense. Pharmacogenetic research, thereby, stands in many cases at the threshold to clinical applicability and in many cases, for instance for the genotyping for thiopurine methyltransferase polymorphisms prior to azathioprine therapy or of dihydropyrimidine dehydrogenase polymorphisms prior to treatment with 5-fluorouracil, as well as for diagnostics of CYP2D6 before therapy with certain tricyclic antidepressants and neuroleptics, one would ask already today whether a such drug therapy is still responsible without pharmacogenetic diagnostics.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 11/2006; 49(10):995-1003. · 0.66 Impact Factor
