Skip to main content
SpringerLink
Log in

Pharmakogenomik

Was ist für den Internisten relevant?

  • Schwerpunkt: Was ist gesichert in der Therapie?
  • Published:
Der Internist Aims and scope Submit manuscript

Zusammenfassung

Aus epidemiologischen Beobachtungsstudien geht hervor, dass ausgeprägte interindividuelle und interethnische Unterschiede im Metabolismus von Pharmaka existieren. Daraus ergibt sich eine große Wirkungs- und Nebenwirkungsbreite von Arzneimitteln. Eine Ursache dieser Variabilitäten liegt in genetischen Polymorphismen, die auf der Basis von Einzelnukleotidaustauschen oder Insertions- und Deletionsmutationen stattfinden können. Mutationen können Transportproteine oder metabolisierende Enzyme der Phase-I- und Phase-II-Reaktionen betreffen, wie es an Beispielen der Cytochrome P450, Glukuronidasen und zytostatikametabolisierender Enzyme näher dargestellt wird. Die daraus resultierenden Unterschiede der Pharmakokinetik und Pharmakodynamik wirken sich auf den Therapieerfolg aus. Anhand moderner Genotypisierungstests ist es nun beispielsweise in der Onkologie möglich, Dosisanpassungen vor Therapiebeginn vorzunehmen, um lebensbedrohliche unerwünschte Arzneimittelwirkungen zu vermeiden. An Beispielen kardiovaskulärer und neurologischer Erkrankungen wird gezeigt, wie genetische Muster die Erkrankungsinzidenz und -prävalenz und Ansprechbarkeit auf Medikamente (β-Blocker, ACE-Hemmer, Psychopharmaka) beeinflussen. Weitere unterschiedliche Faktoren spielen bei der großen Vielfalt von Arzneimittelreaktionen eine Rolle.

Abstract

Epidemiological observational studies have shown existing interindividual and interethnical differences in drug metabolism. This results in a great variety of effects and side effects of drugs. One reason for these variabilities are genetic polymorphisms which occur on the basis of single-nucleotide exchanges or insertional and deletional mutations. Such mutations may involve transport proteins or metabolizing enzymes of phase I and phase II reactions, as cytochrome P450, glucuronidases and enzymes which metabolize cytostatics. The differences in pharmacokinetics and pharmacodynamics have an impact on therapeutical outcome. Dosage adjustments should be undertaken before the initiation of therapy in reflection of modern genotyping. This is particularly important in oncology to avoid life-threatening adverse drug reactions. Examples of cardiovascular and neurological diseases are presented to demonstrate the impact of genetic polymorphisms on the incidence and prevalence of diseases as well as the responses to medications like beta blockers, ACE inhibitors and psychotropic drugs. Finally, additional factors are summarized, which may contribute to the large diversity of drug reactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1.
Abb. 2.

Literatur

  1. Asai S, Miyachi H, Kobayashi H, Takemura Y, Ando Y (2003) Large diversity in transport-mediated methotrexate resistance in human leukemia cell line CCRF-CEM established in a high concentration of leucovorin. Cancer Sci 94: 210–214

    CAS  PubMed  Google Scholar 

  2. Bertilsson L, Dahl ML, Tybring G (1997) Pharmacogenetics of antidepressants: clinical aspects. Acta Psychiatr Scand Suppl 391: 14–21

    CAS  PubMed  Google Scholar 

  3. Burchell B (2003) Genetic variation of human UDP-glucuronyltransferase implications in disease and drug glucuronidation. Am J Pharmacogenomics 3: 37–52

    Google Scholar 

  4. Chiusolo P, Reddiconto G, Casorelli I et al. (2002) Preponderance of methylentatrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 13: 1915–1918

    Article  CAS  PubMed  Google Scholar 

  5. Dalen P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L (1998) 10-Hydroxylation of nortriptyline in white persons with 0,1,2,3 and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63: 444–452

    Google Scholar 

  6. Diamond J (2003) The double puzzle of diabetes. Nature 423: 599–602

    Article  CAS  PubMed  Google Scholar 

  7. Feuerstein G, Kollek R, Schmedders M, Aken JP van (2003) Irreführende Leitbilder. Zum Mythos der Individualisierung durch pharmakogenetische Behandlungskonzepte. Eine kritische Anmerkung. Ethik Med 15: 1–8

    Google Scholar 

  8. Feuring M, Wehling M, Falkenstein E (2000) Beeinflussung der Arzneimittelwirkung durch Erbfaktoren und Erkrankungen. Internist 41: 332–337

    Article  CAS  PubMed  Google Scholar 

  9. Furuta T, Shirai N, Ohashi K, Ishizaki T (2003) Therapeutic impact of CYP2C19 pharmacogenetics on proton pump inhibitor-based eradication therapy for Helicobacter pylori. Methods Find Exp Clin Pharmacol 25: 131–143

    CAS  PubMed  Google Scholar 

  10. Lewis DF, Watson E, Lake BG (1998) Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacogenetics. Mutat Res 410: 245–270

    Article  CAS  PubMed  Google Scholar 

  11. Lin JP, Cupples LA, Wilson PW, Heard-Costa N, O’Donnell CJ (2003) Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham study. Am J Hum Genet 72: 1029–1034

    Article  CAS  PubMed  Google Scholar 

  12. Liston HL, Markowitz JS, De Vane CL (2001) Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 21: 500–515

    Article  CAS  PubMed  Google Scholar 

  13. Mayer B, Schunkert H (2000) ACE-Gen-Polymorphismus und kardiovaskuläre Erkrankungen. Herz 25: 1–6

    CAS  PubMed  Google Scholar 

  14. Meyer UA (1994) Pharmacogenetics: the slow, the rapid, and the ultrarapid. Proc Nat Acad Sci U S A 91: 1983–1984

    CAS  Google Scholar 

  15. Oberdisse E (2001) Pharmakokinetik. In: Oberdisse E, Hackenthal E, Kuschinsky K (Hrsg) Pharmakologie und Toxikologie. Springer, Berlin Heidelberg New York, S 26–28

  16. O’Toole L, Stewart M, Padfield P, Channer K (1998) Effect of the insertion/deletion polymorphism of the angiotensin-converting enzyme inhibitors in patients with heart failure. J Cardiovasc Pharmacol 32: 988–994

    Article  CAS  PubMed  Google Scholar 

  17. Paul NW, Roses AD (2003) Pharmacogenetics and pharmacogenomics: recent developments, their clinical relevance and some ethical, social and legal implications. Springer, Berlin Heidelberg New York Tokio, pp 1–7

    Google Scholar 

  18. Pickar D (2003) Pharmacogenomics of psychiatric drug treatment. Psychiatr Clin North Am 26: 303–321

    PubMed  Google Scholar 

  19. Poolsup N, Li Wan Po A, Knight TL (2000) Pharmacogenetics and Psychopharmacotherapy. J Clin Pharm Ther 25: 197–220

    Article  CAS  PubMed  Google Scholar 

  20. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343–1346

    CAS  PubMed  Google Scholar 

  21. Rudnicki M, Mayer G (2003) Pharmacogenomics of angiotensin converting enzyme inhibitors in renal disease—pathophysiological considerations. Pharmacogenomics 4: 153–162

    CAS  PubMed  Google Scholar 

  22. Sofowora GG, Dishy V, Muszkat M (2003) A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin Pharmacol Ther 73: 366–371

    Article  CAS  PubMed  Google Scholar 

  23. Sparreboom A, Danesi R, Ando Y, Chan J, Figg WD (2003) Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resist Update 6: 71–84

    Article  CAS  Google Scholar 

  24. Staessen JA, Wang JG, Brand E et al. (2001) Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens 19: 1349–1358

    Article  CAS  PubMed  Google Scholar 

  25. Tafti M, Dauvilliers Y (2003) Pharmacogenomics in the treatment of narcolepsy. Pharmacogenomics 4: 23–33

    CAS  PubMed  Google Scholar 

  26. Turner ST, Boerwinkle E (2003) Genetics of blood pressure, hypertensive complications, and antihypertensive drug responses. Pharmacogenomics 4: 53–65

    CAS  PubMed  Google Scholar 

  27. Ulrich CM, Yasui Y, Storb R et al. (2001) Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylentetrahydrofolate reductase C677T polymorphism. Blood 98: 2283–2284

    Article  PubMed  Google Scholar 

  28. Wehling M (2000) Arzneimitteltherapie in der Praxis. Immer ein individuelles Experiment. MMW Fortschr Med 44: 27–28

    Google Scholar 

  29. Wei X, McLeod HL, McMurrough J, Gonzalez FJ, Fernandez-Salguero P (1996) Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest 98: 610–615

    CAS  PubMed  Google Scholar 

  30. Westphal JF, Brogard JM (1997) Drug administration in chronic liver disease. Drug Saf 17: 47–73

    CAS  PubMed  Google Scholar 

  31. Yee LJ, Perez KA, Tang J, van Leeuwen DJ, Kaslow RA (2003) Association of CTLA4 polymorphisms with sustained response to interferon and ribavirin therapy for chronic hepatitis C virus infection. J Infect Dis 187: 1264–1271

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Klinische Pharmakologie, Fakultät für Klinische Medizin Mannheim der Ruprecht-Karls-Universität Heidelberg

    P. Krüth &  M. Wehling

  2. Institut für Klinische Pharmakologie, Fakultät für Klinische Medizin Mannheim, Ruprecht-Karls-Universität Heidelberg, 68135, Mannheim

    M. Wehling

Authors
  1. P. Krüth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Wehling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Wehling.

Additional information

Es besteht kein Interessenkonflikt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krüth, P., Wehling, M. Pharmakogenomik. Internist 44, 1524–1530 (2003). https://doi.org/10.1007/s00108-003-1066-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00108-003-1066-6

Schlüsselwörter

Keywords

Search

Navigation