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Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure

  • Ádám Kiss
  • Ádám Menus
  • Katalin Tóth
  • Máté Déri
  • Dávid Sirok
  • Evelyn Gabri
  • Ales Belic
  • Gábor Csukly
  • István Bitter
  • Katalin Monostory
Original Paper

Abstract

The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients’ CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients’ CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients’ CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy.

Keywords

Aripiprazole therapy CYP2D6 phenoconversion Risperidone Metoprolol Propranolol 

Notes

Acknowledgements

The authors are indebted to Mária Szabó for her skillful assistance in this study. This work was supported by the grants of the National Research, Development and Innovation Office (NKFIH/OTKA K104459 and K104738; VEKOP-2.3.3-15-2017-00014).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Research Centre for Natural Sciences, Institute of EnzymologyHungarian Academy of SciencesBudapestHungary
  2. 2.Department of Psychiatry and PsychotherapySemmelweis UniversityBudapestHungary
  3. 3.Toxi-Coop Toxicological Research CenterBudapestHungary
  4. 4.University of LjubljanaLjubljanaSlovenia

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