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Drug Safety

, Volume 24, Issue 2, pp 75–85 | Cite as

What Will Be the Role of Pharmacogenetics in Evaluating Drug Safety and Minimising Adverse Effects?

Current Opinion

Abstract

In the US, adverse drug reactions (ADRs) rank between the fourth to sixth leading cause of death, ahead of pneumonia and diabetes mellitus. An important reason for the high incidence of serious and fatal ADRs is that the existing drug development paradigms do not generate adequate information on the mechanistic sources of marked variability in pharmacokinetics and pharmacodynamics of new therapeutic candidates, precluding treatments from being tailored for individual patients.

Pharmacogenetics is the study of the hereditary basis of person-to-person variations in drug response. The focus of pharmacogenetic investigations has traditionally been unusual and extreme drug responses resulting from a single gene effect. The Human Genome Project and recent advancements in molecular genetics now present an unprecedented opportunity to study all genes in the human genome, including genes for drug metabolism, drug targets and postreceptor second messenger machinery, in relation to variability in drug safety and efficacy. In addition to sequence variations in the genome, high throughput and genome-wide transcript profiling for differentially regulated mRNA species before and during drug treatment will serve as important tools to uncover novel mechanisms of drug action. Pharmacogenetic-guided drug discovery and development represent a departure from the conventional approach which markets drugs for broad patient populations, rather than smaller groups of patients in whom drugs may work more optimally.

Pharmacogenetics provides a rational framework to minimise the uncertainty in outcome of drug therapy and clinical trials and thereby should significantly reduce the risk of drug toxicity.

Keywords

Drug Response Tardive Dyskinesia Pharmacogenetic Study Global Gene Expression Pattern Pharmacogenetic Inquiry 
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.

Notes

Acknowledgements

Vural Ozdemir is the recipient of a postdoctoral fellowship (Ontario Mental Health Foundation) and a young investigator grant (National Alliance for Research on Schizophrenia and Affective Disorders, New York, US).

References

  1. 1.
    Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: meta-analysis of prospective studies. JAMA 1998; 279: 1200–5PubMedCrossRefGoogle Scholar
  2. 2.
    Drews J. Genomic sciences and the medicine of tomorrow. Nat Biotechnol 1996; 14: 1516–8PubMedCrossRefGoogle Scholar
  3. 3.
    Kleyn PW, Vesell ES. Genetic variation as a guide to drug development. Science 1998; 281: 1820–1PubMedCrossRefGoogle Scholar
  4. 4.
    Kalow W. Pharmacogenetic research: a revolutionary science. J Psychiatry Neurosci 1999; 24: 139–40PubMedGoogle Scholar
  5. 5.
    Weber WW. Populations and genetic polymorphisms. Mol Diagn 1999; 4: 299–307PubMedCrossRefGoogle Scholar
  6. 6.
    Kalow W. Pharmacogenetics: heredity and the response to drugs. 1st edition. Philadelphia: WB Saunders, 1962: 1–231Google Scholar
  7. 7.
    Motulsky AG. Drug reactions, enzymes and biochemical genetics. JAMA 1957; 165: 835–7CrossRefGoogle Scholar
  8. 8.
    Grant DM. Pharmacogenomics and the changing face of clinical pharmacology. Can J Clin Pharmacol 1999; 6: 131–2PubMedGoogle Scholar
  9. 9.
    Sadée W. Genomics and drugs: finding the optimal drug for the right patient. Pharm Res 1998; 15: 959–63PubMedCrossRefGoogle Scholar
  10. 10.
    Kurth JH. Pharmacogenomics: future promise of a tool for identifying patients at risk. Drug Info J 2000; 34: 223–7CrossRefGoogle Scholar
  11. 11.
    Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 1999; 56: 247–58PubMedCrossRefGoogle Scholar
  12. 12.
    Mancinelli L, Cronin M, Sadée W. Pharmacogenomics: the promise of personalized medicine. AAPS Pharmsci 2000; 2(1) article 4 [online]. Available at URL: http://www.pharmsci.org/ [Acessed 2000 Dec 19]
  13. 13.
    Nebert DW. Suggestions for the nomenclature of human alleles: relevance to ecogenetics, pharmacogenetics and molecular epidemiology. Pharmacogenetics 2000; 10: 279–90PubMedCrossRefGoogle Scholar
  14. 14.
    Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 1999; 20: 342–9PubMedCrossRefGoogle Scholar
  15. 15.
    Eaton DL, Farin F, Omiecinski CJ, et al. Genetic susceptibility. In: Rom WN, editor. Environmental and Occupational Medicine, 3rd ed. Philadelphia (PA): Williams & Wilkins, 1998: 209–21Google Scholar
  16. 16.
    Nebert DW. Pharmacogenetics: 65 candles on the cake. Pharmacogenetics 1997; 7: 435–40CrossRefGoogle Scholar
  17. 17.
    Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192–209PubMedCrossRefGoogle Scholar
  18. 18.
    Sjöqvist F. The past, present and future of clinical pharmacology. Eur J Clin Pharmacol 1999; 55: 553–7PubMedCrossRefGoogle Scholar
  19. 19.
    Bertilsson L, Dahl ML. Polymorphic drug oxidation. Relevance to the treatment of psychiatric disorders. CNS Drugs 1996; 5: 200–23CrossRefGoogle Scholar
  20. 20.
    Kalow W, Bertilsson L. Interethnic factors affecting drug response. Adv Drug Res 1994; 25: 1–53Google Scholar
  21. 21.
    Kalow W. Pharmacogenetics in biological perspective. Pharmacol Rev 1997; 49: 369–79PubMedGoogle Scholar
  22. 22.
    Brøsen K. Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry. Ther Drug Monit 1996; 18: 393–6PubMedCrossRefGoogle Scholar
  23. 23.
    Flockhart DA, Oesterheld JR. Cytochrome P450-mediated drug interactions. Child Adolesc Psychiatr Clin N Am 2000; 9: 43–76PubMedGoogle Scholar
  24. 24.
    Pollock BG, Mulsant BH, Sweet RA, et al. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31: 327–31PubMedGoogle Scholar
  25. 25.
    Alfaro CL, Lam YW, Simpson J, et al. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol 2000; 40: 58–66PubMedCrossRefGoogle Scholar
  26. 26.
    Sindrup SH, Brøsen K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 1995; 5: 335–46PubMedCrossRefGoogle Scholar
  27. 27.
    Lin KM, Anderson D, Poland RE. Ethnicity and psychopharmacology. Bridging the gap. Psychiatr Clin North Am 1995; 18: 635–47PubMedGoogle Scholar
  28. 28.
    Yuan R, Parmelee T, Balian JD, et al. In vitro metabolic interaction studies: experience of the food and drug administration. Clin Pharmacol Ther 1999; 66: 9–15PubMedCrossRefGoogle Scholar
  29. 29.
    White RE. Short- and long-term projections about the use of drug metabolism in drug discovery and development. Drug Metab Disp 1998; 26: 1213–6Google Scholar
  30. 30.
    Bechtel PR, Alvan G. Criteria for the choice and definition of healthy volunteers and of patients for phase I and phase II studies in drug development. Eur J Clin Pharmacol 1989; 36: 549–50PubMedCrossRefGoogle Scholar
  31. 31.
    Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441–6PubMedGoogle Scholar
  32. 32.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24: 475–90PubMedGoogle Scholar
  33. 33.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23PubMedGoogle Scholar
  34. 34.
    Okey AB. Enzyme induction in the cytochrome P-450 system. Pharmacol Ther 1990; 45: 241–98PubMedCrossRefGoogle Scholar
  35. 35.
    Tavadia SM, Mydlarski PR, Reis MD, et al. Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol 2000; 42: 628–32PubMedGoogle Scholar
  36. 36.
    Spire-Vayron de la Moureyre C, Debuysere H, Mastain B, et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol 1998; 125: 879–87CrossRefGoogle Scholar
  37. 37.
    Weinshilboum RM. Methylation pharmacogenetics: thiopurine methyltransferase as a model system. Xenobiotica 1992; 22: 1055–71PubMedCrossRefGoogle Scholar
  38. 38.
    Chou WH, Yan FX, de Leon J, et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphismon outcome and costs associated with severe mental illness. J Clin Psychopharmacol 2000; 20: 246–51PubMedCrossRefGoogle Scholar
  39. 39.
    Costa LG. The emerging field of ecogenetics. Neurotoxicol 2000; 21: 85–90Google Scholar
  40. 40.
    Eaton DL. Biotransformation enzyme polymorphism and pesticide susceptibility. Neurotoxicol 2000; 21: 101–11Google Scholar
  41. 41.
    Kalow W, Tang BK. Caffeine as a metabolic probe: exploration of the enzyme-inducing effects of cigarette smoking. Clin Pharmacol Ther 1991; 49: 44–8PubMedCrossRefGoogle Scholar
  42. 42.
    Sachse C, Brockmoller J, Bauer S, et al. Functional significance of a C—>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 1999; 47: 445–9PubMedCrossRefGoogle Scholar
  43. 43.
    Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John’s wort. Lancet 2000; 355: 547–8PubMedCrossRefGoogle Scholar
  44. 44.
    Roby CA, Anderson GD, Kantor E, et al. St John’sWort: effect on CYP3A4 activity. Clin Pharmacol Ther 2000; 67: 451–7PubMedCrossRefGoogle Scholar
  45. 45.
    Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66: 338–45PubMedCrossRefGoogle Scholar
  46. 46.
    Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41–57PubMedCrossRefGoogle Scholar
  47. 47.
    Weber WW. Pharmacogenetics. New York (NY): Oxford University Press, 1997: 41–70Google Scholar
  48. 48.
    Hoffmeyer S, Burk O, von Richter O, et al. 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 U S A 2000; 97: 3473–8PubMedCrossRefGoogle Scholar
  49. 49.
    von Moltke LL, Greenblatt DJ. Drug transporters in psychopharmacology—are they important? J Clin Psychopharmacol 2000; 20: 291–4CrossRefGoogle Scholar
  50. 50.
    Kim RB, Wandel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408–14PubMedCrossRefGoogle Scholar
  51. 51.
    Eichler HG, Müller M. Drug distribution. The forgotten relative in clinical pharmacokinetics. Clin Pharmacokinet 1998; 34: 95–9PubMedCrossRefGoogle Scholar
  52. 52.
    Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to Mdr1a p-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22: 380–7PubMedCrossRefGoogle Scholar
  53. 53.
    Levy G. Predicting effective drug concentrations for individual patients. Determinants of pharmacodynamic variability. Clin Pharmacokinet 1998; 34: 323–33PubMedCrossRefGoogle Scholar
  54. 54.
    Arranz MJ, Kerwin RW. Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment. Ann Med 2000; 32: 128–33PubMedCrossRefGoogle Scholar
  55. 55.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487–91PubMedCrossRefGoogle Scholar
  56. 56.
    Lima JJ, Thomason DB, Mohamed MHN, et al. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999; 65: 519–25PubMedCrossRefGoogle Scholar
  57. 57.
    Propping P, Nothen MM. Genetic variation of CNS receptors - a new perspective for pharmacogenetics. Pharmacogenetics 1995; 5: 318–25PubMedCrossRefGoogle Scholar
  58. 58.
    Basile VS, Masellis M, Badri F, et al. Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 1999; 21: 17–27PubMedCrossRefGoogle Scholar
  59. 59.
    Segman R, Neeman T, Heresco-Levy U, et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 1999; 4: 247–53PubMedCrossRefGoogle Scholar
  60. 60.
    Steen VM, Lovlie R, MacEwan T, et al. Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 1997; 2: 139–45PubMedCrossRefGoogle Scholar
  61. 61.
    Meyer UA, Amrein R, Balant LP, et al. Antidepressants and drug-metabolizing enzymes - expert group report. Acta Psychiatr Scand 1996; 93: 71–9PubMedCrossRefGoogle Scholar
  62. 62.
    Peck CC, Barr WH, Benet LZ, et al. Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. Clin Pharmacol Ther 1992; 51: 465–73PubMedCrossRefGoogle Scholar
  63. 63.
    Halushka MK, Fan JB, Bentley K, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239–47PubMedCrossRefGoogle Scholar
  64. 64.
    Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265: 2037–48PubMedCrossRefGoogle Scholar
  65. 65.
    Hacia JG, Brody LC, Collins FS. Applications of DNA chips for genomic analysis. Mol Psychiatry 1998; 3: 483–92PubMedCrossRefGoogle Scholar
  66. 66.
    Debouck C, Goodfellow PN. DNA microarrays in drug discovery and development. Nat Genet 1999; 21 Suppl.: 48–50CrossRefGoogle Scholar
  67. 67.
    Hyman SE. The millennium of mind, brain, and behavior. Arch Gen Psychiatry 2000; 57: 88–9PubMedCrossRefGoogle Scholar
  68. 68.
    Trevan JW. The error of determination of toxicity. Proc R Soc Lond B 1927; 101: 483–514CrossRefGoogle Scholar
  69. 69.
    Kalow W, Ozdemir V, Tang BK, et al. The science of pharmacological variability. Clin Pharmacol Ther 1999; 66: 445–7PubMedCrossRefGoogle Scholar
  70. 70.
    Tett SE, Holford NHG, McLachlan AJ. Population pharmacokinetics and pharmacodynamics: an underutilized resource. Drug Info J 1998; 32: 693–710CrossRefGoogle Scholar
  71. 71.
    Sheiner LB. The population approach to pharmacokinetic data analysis: rationale and standard data analysis methods. Drug Metab Rev 1984; 15: 153–71PubMedCrossRefGoogle Scholar
  72. 72.
    Sheiner LB. Learning versus confirming in clinical drug development. Clin Pharmacol Ther 1997; 61: 275–91PubMedCrossRefGoogle Scholar
  73. 73.
    Sheiner LB. The intellectual health of clinical drug evaluation. Clin Pharmacol Ther 1991; 50: 4–9PubMedCrossRefGoogle Scholar
  74. 74.
    Kalow W, Tang BK, Endrenyi L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics 1998; 8: 283–9PubMedCrossRefGoogle Scholar
  75. 75.
    Ozdemir V, Kalow W, Tang BK, et al. Evaluation of the genetic contribution to CYP3A4 activity in vivo: A repeated drug administration method. Pharmacogenetics 2000; 10: 373–88PubMedCrossRefGoogle Scholar
  76. 76.
    Hugo V. Histoire D’un Crime, 1st ed. Paris: J. Hetzel & Cie, [189-?]: 1–243Google Scholar
  77. 77.
    Strausberg RL, Austin MJF. Functional genomics: technological challenges and opportunities. Physiol Genomics 1999; 1: 25–32PubMedGoogle Scholar
  78. 78.
    Motulsky AG. If I had a gene test, what would I have and who would I tell? Lancet 1999; 354 Suppl. 1: S35–7CrossRefGoogle Scholar
  79. 79.
    Jonsen AR, Durfy SJ, Burke W, et al. The advent of the ‘unpatients’. Nat Med 1996; 2: 622–4PubMedCrossRefGoogle Scholar
  80. 80.
    Collins FS, Bochm K. Avoiding casualties in the genetic revolution: the urgent need to educate physicians about genetics. Acad Med 1999; 74: 48–9PubMedGoogle Scholar
  81. 81.
    Hinderling PH. Detection of populations at risk and problem drug during drug development and in pharmacotherapy. Ther Drug Monit 1988; 10: 245–9PubMedCrossRefGoogle Scholar
  82. 82.
    Shi MM, Bleavins MR, de la Inglesia FA. Technologies for detecting genetic polymorphisms in pharmacogenomics. Mol Diagn 1999; 4: 343–51PubMedCrossRefGoogle Scholar
  83. 83.
    Chichon S, Nothen MM, Reitschel M, et al. Pharmacogenetics of schizophrenia. Am J Med Genet 2000; 97: 98–106CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of TorontoToronto, OntarioCanada
  2. 2.Department of PsychiatryUniversity of TorontoToronto, OntarioCanada
  3. 3.Division of Clinical Pharmacology, Sunnybrook and Women’s Health Sciences CentreUniversity of TorontoToronto, OntarioCanada

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