Download PDF
Kinder- und Jugendmedizin 2004; 4(05): 161-167
DOI: 10.1055/s-0037-1617830
Schmerz
Schattauer GmbH

Pharmakogenetik und pädiatrische Schmerztherapie

Pharmacogenetics and pediatric pain management
Ulrike Stamer
1   Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Rheinische Friedrich-Wilhelms-Universität Bonn (Direktor: Prof. Dr. med. A. Hoeft)
,
Frank Stüber
1   Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Rheinische Friedrich-Wilhelms-Universität Bonn (Direktor: Prof. Dr. med. A. Hoeft)
› Author Affiliations
Further Information

Publication History

Publication Date:
10 January 2018 (online)

    Permissions and Reprints

Zusammenfassung

Neue Erkenntnisse über die Struktur des Genoms und die Entdeckung genomischer Varianten haben die genetische Diagnostik sowohl für komplexe und akute Erkrankungen als auch für den Bereich Pharmakogenetik interessant werden lassen.

Für einige Bereiche, z. B. der großen Gruppe der metabolisierenden Enzyme, liegen schon Untersuchungen vor, die zeigen, dass genetische Varianten einen Einfluss auf Effektivität und Nebenwirkungen von Arzneimitteln haben. So erfahren Patienten mit einer Defizienz für das Cytochrom P450-Isoenzym 2D6 keine oder nur eine reduzierte Analgesie durch Codein und Tramadol. Auch für die Wirksamkeit und die Nebenwirkungen von Nichtopioid-Analgetika können genetische Varianten eine Rolle spielen.

Erkenntnisse aus dem Bereich der Pharmakogenetik werden es in Zukunft erlauben, die Therapie der individuellen (genetischen) Konstellation anzupassen.

Summary

The human genome project has revealed data on genomic variation which may influence the pharmacological responses. In pain therapy, the genetic background influencing the efficacy of opioid therapy is of special interest. Screening for variations in expression of drug metabolizing enzymes has been suggested as a potential tool for improving the quality of therapy. CYP2D6 genetic variability is supposed to be a major factor of adverse drug reaction, possibly influencing length of hospital stay and total treatment costs. Further candidate genes involved in pain perception, pain processing and pain management like opioid receptors, transporters and other targets of pharmacotherapy are under investigation.

In the future, genetic differences influencing efficacy, side effects and adverse outcome of pharmacotherapy will become important aspects for optimal pain management.

Schlüsselwörter

Genetik - metabolisierende Enzyme - Cytochrom P450 - Tramadol - Codein - Paracetamol

Keywords

Genetics - metabolizing enzymes - cytochrom P450 - tramadol - codeine - acetaminophen
 

  • Literatur

  • 1 Bauer J. Arzneimittelunverträglichkeit. Wie man Betroffene herausfischt. Deutsches Ärzteblatt 2003; 100 (24) B1372-3.
    Google Scholar
  • 2 Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 2001; 276 (05) 3130-7.
    CrossrefPubMedGoogle Scholar
  • 3 Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L. et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 1998; 95 (16) 9608-13.
    CrossrefPubMedGoogle Scholar
  • 4 Bonicke R, Reif W. Enzymatic inactivation of isonicotinic acid hydrizide in human and animal organism. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1953; 220 (04) 321-3.
    PubMedGoogle Scholar
  • 5 Brenner SS, Herrlinger C, Dilger K, Murdter TE, Hofmann U, Marx C, Klotz U. Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Clin Pharmacokinet 2003; 42 (03) 283-92.
    CrossrefPubMedGoogle Scholar
  • 6 Collart L, Luthy C, Favario-Constantin C, Dayer P. Duality of the analgesic effect of tramadol in humans. Schweiz Med Wochenschr 1993; 123 (47) 2241-3.
    PubMedGoogle Scholar
  • 7 Daly AK, Brockmoller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ. et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996; 6 (03) 193-201.
    CrossrefPubMedGoogle Scholar
  • 8 Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, Lerena A. CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 2003; 59: 221-5.
    CrossrefPubMedGoogle Scholar
  • 9 Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998; 76: 27-33.
    CrossrefPubMedGoogle Scholar
  • 10 Fagerlund TH, Braaten O. No pain relief from codeine...? An introduction to pharmacogenomics. Acta Anaesthesiol Scand 2001; 45: 140-9.
    Google Scholar
  • 11 Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 1991; 48: 943-50.
    PubMedGoogle Scholar
  • 12 Henderson CJ, Wolf CR, Kitteringham N, Powell H, Otto D, Park BK. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proc Natl Acad Sci U S A 2000; 97: 12741-5.
    CrossrefPubMedGoogle Scholar
  • 13 Hoehe MR, Kopke K, Wendel B, Rohde K, Flachmeier C, Kidd KK. et al. Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet 2000; 9: 2895-908.
    CrossrefPubMedGoogle Scholar
  • 14 Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 1999; 20: 342-9.
    CrossrefPubMedGoogle Scholar
  • 15 Kirchheimer J, Sasse J, Meineke I, Roots I, Brockmoller J. Trimipramine pharmacogenetics after intravenous and oral administration in carriers of CYP2D genotypes predicting poor, extensive and ultrahigh activity. Pharmacogenetics 2003; 13: 721-8.
    CrossrefPubMedGoogle Scholar
  • 16 Kirchheimer J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 genetic polymorphisms on pharmakogenetics of celebrex and its metabolites. Pharmacogenetics 2003; 13: 473-80.
    CrossrefPubMedGoogle Scholar
  • 17 Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brockmoller J. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br J Clin Pharmacol 2003; 55: 51-61.
    CrossrefPubMedGoogle Scholar
  • 18 Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997; 26 (Suppl. 02) 12-21.
    CrossrefPubMedGoogle Scholar
  • 19 Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279 (15) 1200-5.
    CrossrefPubMedGoogle Scholar
  • 20 Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol 2003; 58: 791-4.
    CrossrefPubMedGoogle Scholar
  • 21 Lotsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C. et al. Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?. Anesthesiology 2002; 97: 814-9.
    CrossrefPubMedGoogle Scholar
  • 22 Masubuchi Y, Bourdi M, Reilly TP, Graf ML, George JW, Pohl LR. Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 2003; Apr 25; 304: 207-12.
    CrossrefPubMedGoogle Scholar
  • 23 Mikus G, Trausch B, Rodewald C, Hofmann U, Richter K, Gramatte T. et al. Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype. Clin Pharmacol Ther 1997; 61: 459-66.
    CrossrefPubMedGoogle Scholar
  • 24 Paar WD, Poche S, Gerloff J, Dengler HJ. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997; 53 (3-4): 235-9.
    CrossrefPubMedGoogle Scholar
  • 25 Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 2001; 286: 2270-9.
    CrossrefPubMedGoogle Scholar
  • 26 Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636-44.
    CrossrefPubMedGoogle Scholar
  • 27 Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51: 289-95.
    CrossrefPubMedGoogle Scholar
  • 28 Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993; 267: 331-40.
    PubMedGoogle Scholar
  • 29 Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60: 284-95.
    PubMedGoogle Scholar
  • 30 Sindrup SH, Brosen K, Bjerring P, Arendt-Nielsen L, Larsen U, Angelo HR. et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1990; 48 (06) 686-93.
    CrossrefPubMedGoogle Scholar
  • 31 Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A. et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003; 105: 231-8.
    CrossrefPubMedGoogle Scholar
  • 32 Steen VM, Andreassen OA, Daly AK, Tefre T, Borresen AL, Idle JR. et al. Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 1995; 5 (04) 215-23.
    CrossrefPubMedGoogle Scholar
  • 33 Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, Rose MJ, Gelmann A, Greenberg HE, De Lepeleire I, Van Hecken A, De Schepper PJ, Ebel DL, Schwartz JI, Rodrigues AD. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 2001; 11: 223-35.
    CrossrefPubMedGoogle Scholar
  • 34 Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric medicine. Br J Anaesth 2001; 86: 413-21.
    CrossrefPubMedGoogle Scholar
  • 35 Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth 2002; 89 (06) 839-45.
    CrossrefPubMedGoogle Scholar
  • 36 Zhang J, Huang W, Chua SS, Wei P, Moore DD. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 2002; 11: 298 (5592): 422-4.
    Google Scholar