Skip to main content
Log in

The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs

Pharmacokinetic and Therapeutic Implications

Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Several different factors, including pharmacogenetics, contribute to inter-individual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of AEDs. With regard to the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of interest. This review summarises the evidence as to whether such polymorphisms affect the clinical action of AEDs. In the case of mephenytoin, defects in its metabolism may be attributable to >10 mutated alleles (designated as *2, *3 and others) of the gene expressing CYP2C19. Consequently, poor metabolisers (PMs) and extensive metabolisers (EMs) could be differentiated, whose frequencies vary among ethnic populations. CYP2C19 contributes to the metabolism of diazepam and phenytoin, the latter drug also representing a substrate of CYP2C9, with its predominant variants being defined as *2 and *3. For both AEDs, there is maximally a 2-fold difference in the hepatic elimination rate (e.g. clearance) or the AUC between the extremes of EMs and PMs which, in the case of phenytoin (an AED with a narrow ‘therapeutic window’), would suggest a dosage reduction only for patients who are carriers of mutated alleles of both CYP2C19 and CYP2C9, a subgroup that is very rare among Caucasians (about 1% of the population) but more frequent in Asians (about 10%). The minor contribution of CYP2C19 to the metabolism of phenobarbital (phenobarbitone) can be overlooked. In rare cases, valproic acid can be metabolised to the reactive (hepatotoxic) metabolite, 4-ene-valproic acid. It is not yet clear whether genetic variants of the involved enzyme (CYP2C9) are responsible for this problem. Likewise, the active metabolite of carbamazepine, carbamazepine-10, 11-epoxide, is transformed by the microsomal epoxide hydrolase, an enzyme that is also highly polymorphic, but the pharmacokinetic and clinical consequences still need to be evaluated.

Pharmacogenetic investigations have increased our general knowledge of drug disposition and action. As for old and especially new AEDs the pharmacogenetic influence on their metabolism is not very striking, it is not surprising that there are no treatment guidelines taking pharmacogenetic data into account. Therefore, the traditional and validated therapeutic drug monitoring approach, representing a direct ‘phenotype’ assessment, still remains the method of choice when an individualised dosing regimen is anticipated. Nevertheless, pharmacogenetics and pharmacogenomics can offer some novel contributions when attempts are made to maximise drug efficacy and enhance drug safety.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII

References

  1. Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Expert Opin Invest Drugs 2006; 15: 637–47

    Article  CAS  Google Scholar 

  2. Neels HM, Sierens AC, Naelaerts K, et al. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab 2004; 42: 1228–55

    CAS  Google Scholar 

  3. Johannessen SI. Can pharmacokinetic variability be controlled for the patient’s benefit? The place of TDM for new AEDs. Ther Drug Monit 2005; 27: 710–3

    Article  PubMed  CAS  Google Scholar 

  4. Herrlinger C, Klotz U. Drug metabolism and drug interactions in the elderly. Best Pract Res Clin Gastroenterol 2001; 15: 897–918

    Article  PubMed  CAS  Google Scholar 

  5. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211–21

    Article  PubMed  CAS  Google Scholar 

  6. Williams JA, Johnson K, Paulauskis J, et al. So many studies, too few subjects: establishing functional relevance of genetic polymorphisms on pharmacokinetics. J Clin Pharmacol 2006; 46: 258–64

    Article  PubMed  CAS  Google Scholar 

  7. Pirazzoli A, Recchia G. Pharmacogenetics and pharmacogenomics: are they still promising? Pharmacol Res 2004; 49: 357–61

    Article  PubMed  CAS  Google Scholar 

  8. Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogen J 2006; 6: 162–5

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  10. Lewis LD. Editors’ view: personalized drug therapy; the genome, the chip and the physician. Br J Clin Pharmacol 2005; 60: 1–4

    Article  PubMed  Google Scholar 

  11. Bonicke R, Lisboa BP. Über die Erbbedingtheit der intraindividuellen Konstanz der Isoniazidausscheidung beim Menschen. Naturwissenschaften 1957; 44: 314–20

    Article  CAS  Google Scholar 

  12. Fischer C, Klotz U. High-performance liquid chromatographic determination of aminosalicylate, sulfapyridine and their metabolites: its application for pharmacokinetic studies with salicylazosulfapyridine in man. J Chromatogr Biomed Appl 1979; 162: 237–43

    Article  CAS  Google Scholar 

  13. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. TRENDs Pharmacol Sci 2004; 25: 193–200

    Article  PubMed  CAS  Google Scholar 

  14. Alexanderson B, Evans DA, Sjöqvist F. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 1969; 4: 764–8

    Article  PubMed  CAS  Google Scholar 

  15. Eichelbaum M. Ein neuentdeckter Defekt im Arzneimittelstoffwechsel des Menschen: die fehlende N-Oxidation des Spartein [thesis]. Bonn: Universität Bonn, 1975

    Google Scholar 

  16. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; 2: 584–6

    Article  PubMed  CAS  Google Scholar 

  17. Cytochrome P450 drug-interaction table [online]. Available from URL: http://medicine.iupui.edu/flockhart/table.htm [Accessed 2007 Feb 27]

  18. Andersson T, Flockhart DA, Goldstein DB, et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005; 78: 559–81

    Article  PubMed  CAS  Google Scholar 

  19. Küpfer A, Desmond P, Patwardhan R, et al. Mephenytoin hydroxylation deficiency: kinetics after repeated doses. Clin Pharmacol Ther 1984; 35: 33–9

    Article  PubMed  Google Scholar 

  20. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP)2D6 and 2C19. Clin Pharmacokinet 1995; 29: 192–209

    Article  PubMed  CAS  Google Scholar 

  21. Xie H-G, Stein CM, Kim RB, et al. Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenet 1999; 9: 539–49

    Article  CAS  Google Scholar 

  22. Rodrigues AD. Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Disp 2005; 33: 1567–75

    Article  CAS  Google Scholar 

  23. Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1–16

    Article  PubMed  CAS  Google Scholar 

  24. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol 2006; 13: 445–50

    Article  PubMed  CAS  Google Scholar 

  25. Walker DM, Teach SJ. Update on the acute management of status epilepticus in children. Curr Opin Pediatr 2006; 18: 239–44

    Article  PubMed  Google Scholar 

  26. Bertilsson L, Baillie TA, Reviriego J. Factor influencing the metabolism of diazepam. Pharmac Ther 1990; 45: 85–91

    Article  CAS  Google Scholar 

  27. Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994; 38: 131–7

    Article  PubMed  CAS  Google Scholar 

  28. Bertilsson L, Henthorn T, Sanz TK, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55

    Article  PubMed  CAS  Google Scholar 

  29. Desta Z, Zhao X, Shin J-G, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913–58

    Article  PubMed  CAS  Google Scholar 

  30. Inomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther 2005; 78: 647–55

    Article  PubMed  CAS  Google Scholar 

  31. Mamiya K, Hadama A, Yukawa E, et al. CYP2C19 polymorphism effect on phenobarbitone: pharmacokinetics in Japanese patients with epilepsy. Analysis by population pharmacokinetics. Eur J Clin Pharmacol 2000; 55: 821–5

    Article  PubMed  CAS  Google Scholar 

  32. Mamiya k, Ieiri I, Shimamoto J, et al. The effects of polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998; 39: 1317–23

    Article  PubMed  CAS  Google Scholar 

  33. Bajpai M, Roskos LK, Shen DD, et al. Roles of cytochrome P450 2C9 and cytochrome P450 2C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Disp 1996; 24: 1401–3

    CAS  Google Scholar 

  34. Kidd RS, Curry TB, Gallagher S, et al. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenet 2001; 11: 803–8

    Article  CAS  Google Scholar 

  35. Aynacioglu AS, Brockmöller J, Bayer S, et al. Frequency of cytochrome P450 CYP2 C19 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 1999; 48: 409–15

    Article  PubMed  CAS  Google Scholar 

  36. Rosemary J, Surendiran A, Rajan S, et al. Influence of the CYP2C9 and CYP2C19 polymorphisms on phenytoin hydroxylation in healthy individuals from south India. Indian J Med Res 2006; 123: 665–70

    PubMed  CAS  Google Scholar 

  37. Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. PNAS 2005; 102: 5507–12

    Article  PubMed  CAS  Google Scholar 

  38. Hung C-C, Lin C-J, Chen C-C, et al. Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther Drug Monit 2004; 26: 534–40

    Article  PubMed  CAS  Google Scholar 

  39. Lee AY, Kim MJ, Chey WY, et al. Genetic polymorphism of cytochrome P450 2C9 in 70 diphenylhydantoin-induced cutaneous adverse drug reactions. Eur J Clin Pharmacol 2004; 60: 155–9

    Article  PubMed  CAS  Google Scholar 

  40. Soga Y, Nishimura F, Ohtsuka Y, et al. CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects. Life Sci 2004; 74: 827–34

    Article  PubMed  CAS  Google Scholar 

  41. Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 2001; 16: 660–94

    Google Scholar 

  42. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002; 16: 695–714

    Article  PubMed  CAS  Google Scholar 

  43. Rettie AE, Rettenmeier AW, Howald WN, et al. Cytochrome P450-catalyzed formation of Δ′4-VPA, a toxic metabolite of valproic acid. Science 1987; 235: 890–2

    Article  PubMed  CAS  Google Scholar 

  44. Cotariu D, Zaidman JL. Valproic acid and the liver. Clin Chem 1988; 34: 890–7

    PubMed  CAS  Google Scholar 

  45. Davis R, Peters DH, McTravish D. Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994; 47: 332–72

    Article  PubMed  CAS  Google Scholar 

  46. Sadeque AJM, Fisher MB, Korzekwa KR, et al. Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. J Pharmacol Exp Ther 1999; 283: 698–703

    Google Scholar 

  47. Ho PC, Abbott FS, Zanger UM, et al. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogen J 2003; 3: 335–42

    Article  CAS  Google Scholar 

  48. Tong V, Teng XW, Chang TK, et al. Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci 2005; 86: 427–35

    Article  PubMed  CAS  Google Scholar 

  49. Tomson T, Tybring G, Bertilsson L. Single-dose kinetics and metabolism of carbamazepine-10, 11-epoxide. Clin Pharmacol Ther 1983; 33: 58–65

    Article  PubMed  CAS  Google Scholar 

  50. Nakajima Y, Saito Y, Shiseki K, et al. Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients. Eur J Clin Pharmacol 2005; 61: 25–34

    Article  PubMed  CAS  Google Scholar 

  51. Hung S-I, Chung W-H, Jee S-H, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genom 2006; 16: 297–306

    Article  CAS  Google Scholar 

  52. Depondt C. The potential of pharmacogenetics in the treatment of epilepsy. Eur J Paediatr Neurol 2006; 10: 57–65

    Article  PubMed  Google Scholar 

  53. Ferraro T, Dlugos DJ, Buono RJ. Challenges and opportunities in the application of pharmacogenetics to antileptic drug therapy. Pharmacogenom 2006; 7: 89–103

    Article  CAS  Google Scholar 

  54. Szoeke C, Newton M, Wood JM, et al. Update on pharmacogenetics in epilepsy: a brief review. Lancet Neurol 2006; 5: 189–96

    Article  PubMed  CAS  Google Scholar 

  55. Gardiner SJ, Begg EJ. Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice? Pharmacogenet Genom 2005; 15: 365–9

    Article  CAS  Google Scholar 

  56. Bialer M. The pharmacokinetics and interactions of new antiepileptic drugs. Ther Drug Monit 2005; 27: 722–6

    Article  PubMed  CAS  Google Scholar 

  57. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006; 61: 246–55

    Article  PubMed  CAS  Google Scholar 

  58. Deckers CLP, Knoester PD, de Haan GJ, et al. Selection criteria for the clinical use of the newer antiepileptic drugs. CNS Drugs 2003; 17: 405–21

    Article  PubMed  CAS  Google Scholar 

  59. Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. Curr Opin Neurol 2006; 19: 175–80

    PubMed  Google Scholar 

  60. Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003; 25: 347–63

    Article  PubMed  CAS  Google Scholar 

  61. Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet 2006; 45: 1061–75

    Article  PubMed  CAS  Google Scholar 

  62. Kirchheiner J, Fuhr U, Brockmöller J. pharmacogenetics-based therapeutic recommendations: ready for clinical practice? Nature Rev Drug Discov 2005; 4: 639–47

    Article  CAS  Google Scholar 

  63. Philipps KA, van Bebber SL. Measuring the value of pharmacogenomics. Nat Rev Drug Discov 2005; 4: 500–9

    Article  Google Scholar 

  64. Hamacher M, Apweiler R, Arnold G, et al. HUPO brain proteome project: summary of the pilot phase and introduction of a comprehensive data reprocessing strategy. Proteomics 2006; 6: 4890–8

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The secretarial help of Mrs S. Verhagen is highly appreciated. This work was supported by the Robert Bosch Foundation, Stuttgart, Germany. The author has no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ulrich Klotz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klotz, U. The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs. Clin Pharmacokinet 46, 271–279 (2007). https://doi.org/10.2165/00003088-200746040-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200746040-00001

Keywords

Navigation