Pharmakogenomik in der Praxis

Zusammenfassung

Die Pharmakogenomik befasst sich mit erblich bedingten vor- oder nachteiligen Unterschieden des Ansprechens auf Medikamente. Innerhalb der letzten 10 Jahre häuften sich vor allem in kleinen Studien die Evidenz für einen genetischen Einfluss auf das Ansprechen auf Medikamente. Die Auswirkungen auf das praktische Arbeiten werden allerdings noch immer diskutiert.

In diesem Beitrag sollen etablierte Beispiele dargestellt werden, bie denen pharmakogenetische Techniken die tägliche Arbeit erleichtern können. Die Beispiele beinhalten die Genotypisierung von CYP2D6 in der Antidepressiva-Therapie, die Analyse von TPMT-Varianten für Vorhersage von Mercaptopurin-induziertem Rückgang des Knochenmarks, VKORC1- und CYP2C9-Analysen um die Antikoagulanzien-Gabe besser zu kontrollieren sowie SLCO1B1-Varienten bei Statin-induzierten Myopathien.

Abstract

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate.

The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.

Pharmakogenetik - Pharmakogenomik - Thiopurinmethyltransferase (TPMT) - Arzneimitteltransport - Cytochrom P450 2D6 - Rhabdomyolyse, statininduziert - SLCO1B1

pharmacogenetics - pharmacogenomics - thiopurine Methyltransferase (TPMT) - drug Transport - cytochrome P450 2D6 - rhabdomyolysis, statin-induced - SLCO1B1

Literatur

• 1 Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective.  Blood. 2008;  111 16-24
• 2 Chung W H, Hung S I, Hong H S. et al . Medical genetics: a marker for Stevens-Johnson syndrome.  Nature. 2004;  428 486
• 3 Collet J P, Hulot J S, Pena A. et al . Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.  Lancet. 2009;  373 309-317
• 4 Eichelbaum M, Ingelman-Sundberg M, Evans W E. Pharmacogenomics and individualized drug therapy.  Annu Rev Med. 2006;  57 119-137
• 5 Eichelbaum M, Spannbrucker N, Steincke B. et al . Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.  Eur J Clin Pharmacol. 1979;  16 183-187
• 6 Evans D A. Genetic variations in the acetylation of isoniazid and other drugs.  Ann N Y Acad Sci. 1968;  151 723-733
• 7 Fujita K, Sasaki Y. Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy.  Curr Drug Metab. 2007;  8 554-562
• 8 Gage B F. Pharmacogenetics-based coumarin therapy.  Hematology Am Soc Hematol Educ Program. 2006;  467-473
• 9 Gasche Y, Daali Y, Fathi M. et al . Codeine intoxication associated with ultrarapid CYP2D6 metabolism.  N Engl J Med. 2004;  351 2827-2831
• 10 Giacomini K M, Brett C M, Altman R B. et al . The pharmacogenetics research network: from SNP discovery to clinical drug response.  Clin Pharmacol Ther. 2007;  81 328-345
• 11 Giacomini K M, Krauss R M, Roden D M. et al . When good drugs go bad.  Nature. 2007;  446 975-977
• 12 Goetz M P, Loprinzi C L. A hot flash on tamoxifen metabolism.  J Natl Cancer Inst. 2003;  95 1734-1735
• 13 Goetz M P, Rae J M, Suman V J. et al . Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.  J Clin Oncol. 2005;  23 9312-9318
• 14 Goldstein D B, Tate S K, Sisodiya S M. Pharmacogenetics goes genomic.  Nat Rev Genet. 2003;  4 937-947
• 15 Gonzalez F J, Skoda R C, Kimura S. et al . Characterization of the common genetic defect in humans deficient in debrisoquine metabolism.  Nature. 1988;  331 442-446
• 16 Ho P M, Maddox T M, Wang L. et al . Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.  JAMA. 2009;  301 937-944
• 17 Juurlink D N, Gomes T, Ko D T. et al . A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.  CMAJ. 2009;  180 713-718
• 18 Kalow W, Staron N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers.  Can J Biochem Physiol. 1957;  35 1305-1320
• 19 Karapetis C S, Khambata-Ford S, Jonker D J. et al . K-ras mutations and benefit from cetuximab in advanced colorectal cancer.  N Engl J Med. 2008;  359 1757-1765
• 20 Kawanishi C, Lundgren S, Agren H. et al . Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study.  Eur J Clin Pharmacol. 2004;  59 803-807
• 21 Kuijer P M, Hutten B A, Prins M H. et al . Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism.  Arch Intern Med. 1999;  159 457-460
• 22 Leipold G, Schutz E, Haas J P. et al . Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis.  Arthritis Rheum. 1997;  40 1896-1898
• 23 Link E, Parish S, Armitage J. et al . SLCO1B1 variants and statin-induced myopathy – a genomewide study.  N Engl J Med. 2008;  359 789-799
• 24 Mahgoub A, Idle J R, Dring L G. et al . Polymorphic hydroxylation of Debrisoquine in man.  Lancet. 1977;  2 584-586
• 25 Maitland M L, Vasisht K, Ratain M J. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?.  Trends Pharmacol Sci. 2006;  27 432-437
• 26 Mallal S, Phillips E, Carosi G. et al . HLA-B*5701 screening for hypersensitivity to abacavir.  N Engl J Med. 2008;  358 568-579
• 27 Mardis E R. The impact of next-generation sequencing technology on genetics.  Trends Genet. 2008;  24 133-141
• 28 Musolino A, Naldi N, Bortesi B. et al . Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer.  J Clin Oncol. 2008;  26 1789-1796
• 29 Oldenburg J, Bevans C G, Fregin A. et al . Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles.  Thromb Haemost. 2007;  98 570-578
• 30 Qazim B, Stollberger C, Krugluger W. et al . Dependency of phenprocoumon dosage on polymorphisms in the VKORC1 and CYP2C9 genes.  J Thromb Thrombolysis. 2009;  28 211-214
• 31 Rieder M J, Reiner A P, Gage B F. et al . Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.  N Engl J Med. 2005;  352 2285-2293
• 32 Rosskopf D, Kroemer H K, Siegmund W. [Pharmacokinetic problems in clinical practice: role of drug transporters].  Dtsch Med Wochenschr. 2009;  134 345-356
• 33 Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines.  Eur J Clin Pharmacol. 2008;  64 753-767
• 34 Schroth W, Antoniadou L, Fritz P. et al . Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes.  J Clin Oncol. 2007;  25 5187-5193
• 35 Simon T, Verstuyft C, Mary-Krause M. et al . Genetic determinants of response to clopidogrel and cardiovascular events.  N Engl J Med. 2009;  360 363-375
• 36 Stanulla M, Schaeffeler E, Flohr T. et al . Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.  JAMA. 2005;  293 1485-1489
• 37 Thompson P D, Clarkson P, Karas R H. Statin-associated myopathy.  JAMA. 2003;  289 1681-1690
• 38 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.  Clin Pharmacokinet. 2005;  44 1227-1246
• 39 Urso M L, Clarkson P M, Hittel D. et al . Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins.  Arterioscler Thromb Vasc Biol. 2005;  25 2560-2566
• 40 Zanger U M, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry.  Naunyn Schmiedebergs Arch Pharmacol. 2004;  369 23-37