European Journal of Clinical Pharmacology

, Volume 63, Issue 12, pp 1147–1151 | Cite as

Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole

  • Magnhild Hendset
  • Monica Hermann
  • Hilde Lunde
  • Helge Refsum
  • Espen Molden
Pharmacokinetics and Disposition

Abstract

Objective

Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole (DARI) in psychiatric patients.

Methods

Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3–6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3–6/*3–6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups.

Results

The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs. 37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant for both ARI (p < 0.05) and ARI + DARI (p < 0.05).

Conclusion

The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30–40% lower doses to achieve a similar steady-state serum concentration as EMs.

Keywords

Aripiprazole Dehydroaripiprazole Genotype Serum concentration CYP2D6 

References

  1. 1.
    Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9:442–473PubMedCrossRefGoogle Scholar
  2. 2.
    Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A (2002) Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 53:111–122PubMedCrossRefGoogle Scholar
  3. 3.
    Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23–37PubMedCrossRefGoogle Scholar
  4. 4.
    Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400–1411PubMedCrossRefGoogle Scholar
  5. 5.
    Product information (2006) Abilify (Aripiprazole). Otsuka Pharmaceutical Europe, LondonGoogle Scholar
  6. 6.
    Molden E, Lunde H, Lunder N, Refsum H (2006) Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients. Ther Drug Monit 28:744–749PubMedCrossRefGoogle Scholar
  7. 7.
    Rudberg I, Hendset M, Uthus LH, Molden E, Refsum H (2006) Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Ther Drug Monit 28:102–105PubMedCrossRefGoogle Scholar
  8. 8.
    Schaeffeler E, Schwab M, Eichelbaum M, Zanger UM (2003) CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR. Hum Mutat 22:476–485PubMedCrossRefGoogle Scholar
  9. 9.
    Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63:763–771PubMedGoogle Scholar
  10. 10.
    Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR (2003) Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 60:681–690PubMedCrossRefGoogle Scholar
  11. 11.
    Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T (2003) Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr Res 61:123–136PubMedCrossRefGoogle Scholar
  12. 12.
    Ramaswamy S, Vijay D, William M, Sattar SP, Praveen F, Petty F (2004) Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol 19:45–48PubMedCrossRefGoogle Scholar
  13. 13.
    Oosterhuis M, Van De KG, Tenback D (2007) Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient. Am J Psychiatry 164:175PubMedCrossRefGoogle Scholar
  14. 14.
    Hendset M, Haslemo T, Rudberg I, Refsum H, Molden E (2006) The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs. Pharmacopsychiatry 39:121–127PubMedCrossRefGoogle Scholar
  15. 15.
    de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ (2005) The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 66:15–27PubMedCrossRefGoogle Scholar
  16. 16.
    Kohnke MD, Griese EU, Stosser D, Gaertner I, Barth G (2002) Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone. Pharmacopsychiatry 35:116–118PubMedCrossRefGoogle Scholar
  17. 17.
    Huang ML, Van PA, Woestenborghs R, De CR, Heykants J, Jansen AA, Zylicz Z, Visscher HW, Jonkman JH (1993) Pharmacokinetics of the novel antipsychotic agent risperi1done and the prolactin response in healthy subjects. Clin Pharmacol Ther 54:257–268PubMedCrossRefGoogle Scholar
  18. 18.
    Kubo M, Koue T, Inaba A, Takeda H, Maune H, Fukuda T, Azuma J (2005) Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic ARIPIPRAZOLE. Drug Metab Pharmacokinet 20:55–64PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Magnhild Hendset
    • 1
  • Monica Hermann
    • 1
  • Hilde Lunde
    • 1
  • Helge Refsum
    • 1
  • Espen Molden
    • 1
  1. 1.Department of PsychopharmacologyDiakonhjemmet HospitalOsloNorway

Personalised recommendations