nach oben

Erschienen in:

01.08.2005 | Leitthema: Arzneimitteltherapie

Pharmakogenetik

verfasst von: Prof. Dr. M. Eichelbaum, M. Schwab

Erschienen in: Monatsschrift Kinderheilkunde | Ausgabe 8/2005

Einloggen, um Zugang zu erhalten

Zusammenfassung

Die Pharmakogenetik untersucht, inwieweit genetische Polymorphismen der Proteine, die die pharmakokinetischen und pharmakodynamischen Prozesse eines Arzneimittels kontrollieren, für die interindividuellen Unterschiede in Wirkung und Nebenwirkung verantwortlich sind. Im Gegensatz zur Pharmakogenetik nutzt die Pharmakogenomik einen genomweiten Ansatz zur Identifizierung von Genen bzw. Gennetzwerken, die an der Entstehung von Erkrankungen beteiligt sind bzw. als therapeutische Ziele für neue Arzneistoffe dienen können. Die zurzeit am besten charakterisierten pharmakogenetischen Polymorphismen betreffen die Arzneimittel metabolisierenden Enzyme Zytochrom-P450-2C9, -2C19 und -2D6 bzw. die Thiopurinmethyltransferase, für die in klinischen Studien relevante Konsequenzen für die Arzneimitteltherapie gezeigt werden konnten. Das ultimative Ziel pharmakogenetischer/-genomischer Forschung ist es, unter Verwendung einer neuen Krankheits- und Therapieklassifikation auf molekularer Ebene eine spezifische Arzneimitteltherapie bei genetisch definierten Untergruppen von Patienten durchzuführen.

Ahsen von N, Richter M, Grupp C et al. (2001) No influence of the MDR-1 C3435T polymorphisms or a CYP3A4 promoter polymorphism (CYP3A4-V Allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 47:1048–1052PubMed

Beutler E (1969) Drug induced haemolytik anaemia. Pharmacol Rev 21:73–103PubMed

Black AJ, McLeod HL, Capell HA et al. (1998) Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129:716–718PubMed

Broly F, Gaedigk A, Heim M et al. (1991) Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 10:545–558PubMed

Brøsen K, Morais SMF de, Meyer UA et al. (1995) A multifamily study on the relationship between CYP2C19 genotype and S-mephenytoin oxidation phenotype. Pharmacogenetics 5:312–317PubMed

Chowbay B, Cumaraswamy S, Cheung YB et al. (2003) Genetic polymorphisms im MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporine disposition in heart transplant recipients. Pharmacogenetics 74:245–254

Colombel JF, Ferrari N, Debuysere H et al. (2000) Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 118:1025–1030PubMed

Daly AK, Brockmöller J, Broly F et al. (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6:193–201PubMed

Dishy V, Sofowora GG, Xie HG et al. (2001) The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med 14:1030–1035CrossRef

10.

Drysdale CM, McGraw DW, Stack CB et al. (2000) Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 97:10.483–10.488CrossRefPubMed

11.

Eckhardt K, Li S, Ammon S et al. (1998) Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27–33CrossRefPubMed

12.

Eichelbaum M, Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. Pharmacol Ther 46:377–394CrossRefPubMed

13.

Eichelbaum M, Spannbrucker N, Steincke B et al. (1979) Defective oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 39:533–537

14.

Eichelbaum M (1975) Ein neuentdeckter Defekt im Arzneimittelstoffwechsel des Menschen: Die fehlende N-Oxidation des Spartein. Habilitationsschrift, Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn

15.

Evans WE, Hon YY, Bomgaars L et al. (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19:2293–2301PubMed

16.

Evans WE, Horner M, Chu YQ et al. (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119:985–989PubMed

17.

Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491CrossRefPubMed

18.

Evans WE, Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429:464–468CrossRefPubMed

19.

Fromm MF, Kroemer HK, Eichelbaum M (1997) Impact of P450 genetic polymorphism on the firstpass extraction of cardiovascular and neuroactive drugs. Adv Drug Deliv Rev 27:171–199CrossRefPubMed

20.

Furuta T, Ohashi K, Kamata T et al. (1998) Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 129:1027–1030PubMed

21.

Furuta T, Shirai N, Takashima M et al. (2001) Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69:158–168CrossRefPubMed

22.

Goldstein JA, Faletto MB, Romkes-Sparks M et al. (1994) Evidence that CYP2C19 is the major (S)-mephenytoin 4’-hydroxylase in humans. Biochemistry 33:1743–1752CrossRefPubMed

23.

Gonzalez FJ, Skoda RC, Kimura S et al. (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331:442–446CrossRefPubMed

24.

Gough AC, Miles JS, Spurr NK et al. (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347:773–776CrossRefPubMed

25.

Griese EU, Läpple F, Eichelbaum M (1999) Detection of CYP2C19 alleles *1, *2 and *3 by multiplex polymerase chain reaction. Pharmacogenetics 9:389–391PubMed

26.

Griese EU, Zanger UM, Brudermanns U et al. (1998) Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 8:15–26PubMed

27.

Hauser IA, Schaeffeler E, Gauer S et al. (2005) ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J Am Soc Nephrol 16:1501–1511CrossRefPubMed

28.

Hoffmeyer S, Burk O, von Richter O et al. (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478CrossRefPubMed

29.

Holleman A, Cheok MH, den Boer ML et al. (2004) Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 351:533–542CrossRefPubMed

30.

Ieiri I, Kubota T, Urae A et al. (1996) Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther 59:647–653CrossRefPubMed

31.

Ingelman-Sundberg M, Oscarson M, McLellan RA (1999) Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 20:342–349CrossRefPubMed

32.

Israel E, Drazen JM, Liggett SB et al. (2001) Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma. Int Arch Allergy Immunol 124:183–186CrossRefPubMed

33.

Johansson I, Lundqvist, Bertilsson L (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11.825–11.829PubMed

34.

Johne A, Kopke K, Gerloff T et al. (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594CrossRefPubMed

35.

Johnson JA, Lima JL (2003) Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges. Pharmacogenetics 13:525–534CrossRefPubMed

36.

Kager L, Cheok M, Yang W et al. (2005) Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest 115:110–117CrossRefPubMed

37.

Krynetski EY, Schuetz JD, Galpin AJ et al. (1995) A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 92:949–953PubMed

38.

Krynetski GY, Evans WE (1998) Pharmacogenetics of cancer chemotherapy: getting personal (mini-review). Am J Hum Genet 63:11–16CrossRefPubMed

39.

Küpfer A, Preisig R (1984) Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 26:753–759PubMed

40.

Kurata Y, Ieiri I, Kimura M et al. (2002) Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72:209–221CrossRefPubMed

41.

Lima JJ, Thomason DB, Mohamed MH et al. (1999) Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 5:519–525

42.

Lugthart S, Cheok MH, Boer ML den et al. (2005) Identification of genes associated with chemotherapy cross-resistance and treatment response in childhood acute lymphoblastic leukemia. Cancer Cell 7: 375–386CrossRefPubMed

43.

Mahgoub A, ldle JR, Dring LG (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586CrossRefPubMed

44.

McLeod HL, Krynetski EY, Relling MV et al. (2000) Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14:567–572CrossRefPubMed

45.

McLeod HL, Miller DR, Evans WE (1993) Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 341:1151CrossRef

46.

Meyer UA (2000) Pharmacogenetics and adverse drug reactions. Lancet 356:1667–1671CrossRefPubMed

47.

Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37:269–296CrossRefPubMed

48.

Min DI, Ellingrod VL (2002) C3435T Mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 24:400–404CrossRefPubMed

49.

Mörike K, Magadum S, Mettang T et al. (1995) Propafenone in an usual dose produces severe side effects: the impact of genetically determined metabolic status on drug therapy. J Intern Med 238:469–472PubMed

50.

Mwinyi J, Johne A, Bauer S et al. (2004) Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 75:415–421CrossRefPubMed

51.

Nebert DW (1997) Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 60:265–271PubMed

52.

Nelson DR (1999) Cytochrome P450 and the individuality of species. Arch Biochem Biophys 369:1–10CrossRefPubMed

53.

Niemi M, Neuvonen PJ, Hofmann U et al. (2005) Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet Genomics 15:1–7PubMed

54.

Niemi M, Schaeffeler E, Lang T et al. (2004) High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440PubMed

55.

Nishizato Y, Ieiri I, Suzuki H et al. (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565CrossRefPubMed

56.

Otterness D, Szumlanski C, Lennard L et al. (1997) Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 62:60–73CrossRefPubMed

57.

Raimundo S, Fischer J, Eichelbaum M et al. (2000) Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6. Pharmacogenetics 10:577–581CrossRefPubMed

58.

Relling MV, Hancock ML, Boyett JM et al. (1999) Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93:2817–2823PubMed

59.

Relling MV, Hancock ML, Rivera GK et al. (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008CrossRefPubMed

60.

Rendic S, Di Carlo FJ (1997) Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413–580PubMed

61.

Rettie AE, Koop DR, Haining RL (2000) CYP2C. In: Levy RH, Thummel KE, Trager WF et al. (eds) Metabolic drug interactions. Lippinccott Williams & Wilkins, Philadelphia, Chap 7, pp 75–86

62.

Roberts R, Joyce P, Mjulder RT et al. (2002) A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypertension in patients treated for major depression. Pharmacogenomics J 2:191–196CrossRefPubMed

63.

Rocha JC, Cheng C, Liu W, Kishi S et al. (2005) Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 105:4752–4758CrossRefPubMed

64.

Sachse C, Brockmöller J, Bauer S et al. (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295PubMed

65.

Schaeffeler E, Fischer C, Brockmeier D et al. (2004) Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14:407–417CrossRefPubMed

66.

Siddoway LA, Thompson KA, McAllister CB et al. (1987) Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75:785–791PubMed

67.

Stanulla M, Schaeffeler E, Flohr T et al. (2005) Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293:1485–1489CrossRefPubMed

68.

Tai H-L, Krynetski EY, Yates CR et al. (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58:694–702PubMed

69.

Tirona ERG, Leake BF, Merino G et al. (2001) Polymorphisms in OATP-C. Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276:35.669–35.675CrossRefPubMed

70.

Verstuyft C, Schwab M, Schaeffeler E et al. (2003) Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol 58:809–812PubMed

71.

Vogel F (1959) Moderne Probleme der Humangenetik. Ergeb Inn Med Kinderheilkd 12:52–125

72.

Wagner F, Jähnchen E, Trenk D et al. (1987) Severe complications of antianginal therapy in a patient identified as a poor metabolizer of metoprolol, propafenone, diltiazem, and sparteine. Klin Wochenschr 65:1164–1168CrossRefPubMed

73.

Xie HG, Stein CM, Kim RB et al. (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4’-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549PubMed

74.

Yates CR, Krynetski EY, Loennechen T et al. (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–614PubMed

75.

Zanger UM, Eichelbaum M (2001) Cytochrome P450 2D6. In: Roots I, Gonzalez FJ, Brockmöller J (eds) Pharmacogenetics. Handbook of experimental pharmacology. Springer, Berlin Heidelberg New York, pp 705–712

76.

Zanger UM, Fischer J, Raimundo S et al. (2001) Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 11:573–585CrossRefPubMed

Titel: Pharmakogenetik
verfasst von: Prof. Dr. M. Eichelbaum
M. Schwab
Publikationsdatum: 01.08.2005
Verlag: Springer-Verlag
Erschienen in: Monatsschrift Kinderheilkunde / Ausgabe 8/2005
Print ISSN: 0026-9298
Elektronische ISSN: 1433-0474
DOI: https://doi.org/10.1007/s00112-005-1199-x

Neu im Fachgebiet Pädiatrie

18.04.2024 | Spinale Muskelatrophien | Nachrichten

Update Pädiatrie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Pharmakogenetik

Zusammenfassung

Neu im Fachgebiet Pädiatrie

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Zunahme von Geschlechtsinkongruenz und -dysphorie registriert

Intrakapsuläre Tonsillektomie gewinnt an Boden

Update Pädiatrie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Zusammenfassung

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2005

Noninvasive Diagnostik bei Kindern mit Verdacht auf chronisch-entzündliche Darmerkrankung

Hundebissverletzungen beim Kind

Europäische Initiative „Better Medicines for Children“

Dauerinhalationstherapie für mild-persistierendes Asthma?

Mitteilungen der DGKJ und ÖGKJHK

Amoxicillintrockensäfte

Neu im Fachgebiet Pädiatrie

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Zunahme von Geschlechtsinkongruenz und -dysphorie registriert

Intrakapsuläre Tonsillektomie gewinnt an Boden

Update Pädiatrie