Are Pharmacogenetics and Pharmacogenomics Important for Critically III Patients?

  • C. Kirwan
  • I. MacPhee
  • B. Philips
Conference paper


Drugs are administered to patients using dosing regimens established from animal data, clinical trials, and population studies. However, there may be enormous variation in dose requirement, efficacy, and adverse effects between individuals within a given population. Although this may partly be attributed to factors such as age, concomitant drug interactions, co-morbidities, and the underlying disease itself, genetic factors are estimated to account for 15–30% of between individual differences and for some drugs the impact of genetics may be much higher [1, 2]. Genetic variation may influence all aspects of pharmacokinetics and pharmacodynamics and although the clinical relevance of pharmacogenetics remains uncertain, the idea is developing that some drug therapies may be individualized in the future.


Warfarin Maintenance Dose Poor Metabolizer Phenotype Sodium Lithium Countertransport Midazolam Clearance TPMT Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Evans WE, Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429:464–468PubMedCrossRefGoogle Scholar
  2. 2.
    Weinshilboum R (2003) Inheritance and drug response. N Engl J Med 348:529–537PubMedCrossRefGoogle Scholar
  3. 3.
    Evans WE, Johnson JA (2001) Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu Rev Genomics Hum Genet 2:9–39PubMedCrossRefGoogle Scholar
  4. 4.
    Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491PubMedCrossRefGoogle Scholar
  5. 5.
    McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101–121PubMedCrossRefGoogle Scholar
  6. 6.
    Lander ES, Linton LM, Birren B, et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921PubMedCrossRefGoogle Scholar
  7. 7.
    Kalow W (1956) Familial incidence of low pseudocholinesterase level. Lancet 2:576CrossRefGoogle Scholar
  8. 8.
    Evans WE, McLeod HL (2003) Pharmacogenomics — drug disposition, drug targets, and side effects. N Engl J Med 348:538–549PubMedCrossRefGoogle Scholar
  9. 9.
    Roses AD (2000) Pharmacogenetics and the practice of medicine. Nature 405:857–865PubMedCrossRefGoogle Scholar
  10. 10.
    Wilkins MR, Roses AD, Clifford CP (2000) Pharmacogenetics and the treatment of cardiovascular disease. Heart 84:353–354PubMedCrossRefGoogle Scholar
  11. 11.
    Higashi MK, Veenstra DL, Kondo LM, et al (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690–1698PubMedCrossRefGoogle Scholar
  12. 12.
    Kalow W (1997) Pharmacogenetics in biological perspective. Pharmacol Rev 49:369–379PubMedGoogle Scholar
  13. 13.
    Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225–229PubMedCrossRefGoogle Scholar
  14. 14.
    Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26:186–191PubMedCrossRefGoogle Scholar
  15. 15.
    Lanfear DE, Marsh S, Cresci S, Spertus JA, McLeod HL (2004) Frequency of compound genotypes associated with beta-blocker efficacy in congestive heart failure. Pharmacogenomics 5:553–558PubMedCrossRefGoogle Scholar
  16. 16.
    Quirk E, McLeod H, Powderly W (2004) The pharmacogenetics of antiretroviral therapy: a review of studies to date. Clin Infect Dis 39:98–106PubMedCrossRefGoogle Scholar
  17. 17.
    Siddiqui A, Kerb R, Weale ME, et al (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348:1442–1448PubMedCrossRefGoogle Scholar
  18. 18.
    Gardiner SJ, Begg EJ (2006) Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 58:521–590PubMedCrossRefGoogle Scholar
  19. 19.
    Kuehl P, Zhang J, Lin Y, et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391PubMedCrossRefGoogle Scholar
  20. 20.
    He P, Court MH, Greenblatt DJ, Von Moltke LL (2005) Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 77:373–387PubMedCrossRefGoogle Scholar
  21. 21.
    Ng FL, Holt DW, MacPhee IA (2007) Pharmacogenetics as a tool for optimising drug therapy in solid-organ transplantation. Expert Opin Pharmacother 8:2045–2058PubMedCrossRefGoogle Scholar
  22. 22.
    Hustert E, Haberl M, Burk O, et al (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773–779PubMedCrossRefGoogle Scholar
  23. 23.
    Yu KS, Cho JY, Jang IJ, et al (2004) Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther 76:104–112PubMedCrossRefGoogle Scholar
  24. 24.
    Relling MV, Hoffman JM (2007) Should pharmacogenomic studies be required for new drug approval? Clin Pharmacol Ther 81:425–428PubMedCrossRefGoogle Scholar
  25. 25.
    Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M (2007) Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8: 743–759PubMedCrossRefGoogle Scholar
  26. 26.
    Furuya H, Fernandez-Salguero P, Gregory W, et al (1995) Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 5:389–392PubMedCrossRefGoogle Scholar
  27. 27.
    Takahashi H, Kashima T, Nomizo Y, et al (1998) Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 63:519–528PubMedCrossRefGoogle Scholar
  28. 28.
    Freeman BD, McLeod HL (2004) Challenges of implementing pharmacogenetics in the critical care environment. Nat Rev Drug Discov 3:88–93PubMedCrossRefGoogle Scholar
  29. 29.
    Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD (2002) The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 194:267–273PubMedCrossRefGoogle Scholar
  30. 30.
    Mialet Perez J, Rathz DA, Petrashevskaya NN, et al (2003) Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9: 1300–1305CrossRefGoogle Scholar
  31. 31.
    Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms of beta1and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347:1135–1142PubMedCrossRefGoogle Scholar
  32. 32.
    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 345: 1030–1035PubMedCrossRefGoogle Scholar
  33. 33.
    Dishy V, Landau R, Sofowora GG, et al (2004) Beta2-adrenoceptor Thr164I1e polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo. Pharmacogenetics 14:517–522PubMedCrossRefGoogle Scholar
  34. 34.
    Burgess JK, Lindeman R, Chesterman CN, Chong BH (1995) Single amino acid mutation of Fc gamma receptor is associated with the development of heparin-induced thrombocytopenia. Br J Haematol 91:761–766PubMedCrossRefGoogle Scholar
  35. 35.
    Carlsson LE, Santoso S, Baurichter G, et al (1998) Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism. Blood 92:1526–1531PubMedGoogle Scholar
  36. 36.
    Arepally G, McKenzie SE, Jiang XM, Poncz M, Cines DB (1997) Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 89:370–375PubMedGoogle Scholar
  37. 37.
    Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM (1999) Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99:552–557PubMedGoogle Scholar
  38. 38.
    Cascorbi I, Gerloff T, Johne A, et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69:169–174PubMedCrossRefGoogle Scholar
  39. 39.
    Min DI, Lee M, Ku YM, Flanigan M (2000) Gender-dependent racial difference in disposition of cyclosporine among healthy African American and white volunteers. Clin Pharmacol Ther 68:478–486PubMedCrossRefGoogle Scholar
  40. 40.
    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 Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478PubMedCrossRefGoogle Scholar
  41. 41.
    Schinkel AH, Smit JJ, van Tellingen O, et al (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502PubMedCrossRefGoogle Scholar
  42. 42.
    Coffman BL, Rios GR, King CD, Tephly TR (1997) Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25:1–4PubMedGoogle Scholar
  43. 43.
    Duguay Y, Baar C, Skorpen F, Guillemette C (2004) A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther 75:223–233PubMedCrossRefGoogle Scholar
  44. 44.
    Klepstad P, Rakvag TT, Kaasa S, et al (2004) The 118 A > G polymorphism in the human muopioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232–1239PubMedCrossRefGoogle Scholar
  45. 45.
    Meineke I, Freudenthaler S, Hofmann U, et al (2002) Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol 54: 592–603PubMedCrossRefGoogle Scholar
  46. 46.
    Rakvag TT, Klepstad P, Baar C, et al (2005) The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116:73–78PubMedCrossRefGoogle Scholar
  47. 47.
    DeRijk RH, Schaaf M, de Kloet ER (2002) Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol 81:103–122PubMedCrossRefGoogle Scholar
  48. 48.
    Ameyaw MM, Regateiro F, Li T, et al (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11: 217–221PubMedCrossRefGoogle Scholar
  49. 49.
    Mancinelli LM, Frassetto L, Floren LC, et al (2001) The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 69:24–31PubMedCrossRefGoogle Scholar
  50. 50.
    Michaud J, Dube P, Naud J, et al (2005) Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450. Br J Pharmacol 144:1067–1077PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2008

Authors and Affiliations

  • C. Kirwan
    • 1
  • I. MacPhee
    • 1
  • B. Philips
    • 1
  1. 1.Department of Intensive CareSt George’s University of LondonLondonUK

Personalised recommendations