Pharmacogenetics: reality or fiction? Or are we there yet?

Farmacogenética: realidade ou ficção? Já chegamos lá?

EDITORIAL

Pharmacogenetics: reality or fiction? Or are we there yet?

Farmacogenética: realidade ou ficção? Já chegamos lá?

Iscia Lopes-Cendes^I; Carlos A.M. Guerreiro^II

^IProfessor of Medical Genetics, Department of Medical Genetics. Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas SP, Brazil

^IIProfessor of Neurology, Department of Neurology. Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas SP, Brazil

^{Correspondence}

The paper by Twardowschy et al.¹ is certainly opportune since phenytoin is considered extremely effective as a drug treatment for focal seizures and focal epilepsy syndromes² and it is still one of the most used antiepileptic drugs worldwide, including in the USA³. Experts in the field of epilepsy have a tendency to reduce the use of phenytoin mainly due to its adverse effects and because it is a potent inducer of the hepatic microsomal system which may lead to serious potential drug interactions.

The word pharmacogenetics was first introduced in the late 1950s⁴ and today is used to indicate the existence of DNA sequence variations that may impact the way the body responds to drugs. Overall these DNA variations can occur in genes coding for [i] drug transporters, [ii] enzymes involved in drug metabolism or [iii] in proteins related to drug targets⁵. Over the past decade there has been a greater understanding on how changes in DNA sequence may lead to changes in protein function. This was achieved mainly by the advances in our understanding of the human genome, starting with the completion of the Human Genome Project⁶ and the subsequent studies⁷. However, it remains a major challenge to effectively apply this knowledge into the daily clinical practice. Recently, regulatory agencies approved the clinical use of some pharmacogenetic tests⁸; however, the promise of 'personalized medicine' is still a futuristic vision and for the most skeptical an unattainable reality⁹. In the specific case of antiepileptic drugs a serious allergic cutaneous reactions caused by CBZ therapy was found to be significantly more common in patients with a particular human leukocyte antigen (HLA) allele: HLA-B* 1502. This allele occurs almost exclusively in patients with Asian ancestry. A recent FDA alert recommends that patients withancestry of an at-risk population be screened for the HLA-B* 1502 allele prior to starting CBZ and that positive patients not be exposed to it¹⁰. Controversy aside, the fact of the matter is that experience has taught us that one should never underestimate the complexity of human biology, and this is certainly true for the genetic influences on proteins regulating pharmacokinetic and pharmacodynamic processes which are far from being fully understood. Until then we will have an incomplete view, and therefore subject to error. At this point a more broadly application of pharmacogenetics to clinical practice is still a promise; however, the field offers already opportunity for a very interesting area of scientific investigation as well illustrated by the paper by Twardowschy et al.¹.

• 1. Twardowschy CA, Werneck LC, Scola RH, DePaola L, Silvado CE. CYP2C9 polymorphisms in patients with epilepsy. Genotypic frequency analyzes and phenytoin adverse reactions correlations. Arq Neuropsiquiatr 2011;69:153-158.
• 2. Glauser T, Bem-Menachen E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47: 1094-1120.
• 3. Gidal BE, French JA, Grossman P, Le Teuff G. Assessment of potential drug interactions in patients with epilepsy: Impact of age and sex. Neurology 2009; 72:419-425.
• 4. Vogel F. Moderne probleme der humangenetik. Ergeb Inn Med Kinderheilkd 1959;12:52-125.
• 5. Johnson JA. Pharmacogenetics: potential for individualized drug therapy through genetics. Trends Genet 2003;19:660-666.
• 6. International Human Genome Sequence Consortium. Initial sequencing and analysis of the human genome. Nature 2001;409:860-921.
• 7. Jordan DM, Ramensky VE, Sunyaev SR. Human allelic variation: perspective from protein function, structure, and evolution. Curr Opin Struct Biol 2010;20:342-350.
• 8. Evans BJ. Establishing clinical utility of pharmacogenetic tests in the post-FDAAA era. Clin Pharmacol Ther 2010;88:749-751.
• 9. Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med 2010;363:301-304.
• ¹⁰
  Information for healthcare professionals. Carbamazepine (market as Carbatrol, Equetro, Tegretol and generics). FDA Alert 12/12/07, updated 1/31/08; Available at: http:www.fda.gov/cder/drug/InfoSheet/HCP/carbamazepineHCP.htm Accessed January 10, 2009.

Publication Dates

• Publication in this collection
  26 Apr 2011
• Date of issue
  Apr 2011