Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Editorial Board: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.


CiteScore 2018: 1.01

SCImago Journal Rank (SJR) 2018: 0.277
Source Normalized Impact per Paper (SNIP) 2018: 0.446

Online
ISSN
2363-8915
See all formats and pricing
More options …
Volume 32, Issue 3

Issues

Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration

Dmitry A. Sychev
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mikhail S. Zastrozhin
  • Corresponding author
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, The Department of Addictology, 2/1 Barrikadnaya Street, Moscow 123995, Russian Federation, Phone: +7 968 642 00 92
  • Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, 37/1 Lyublinskaya street, Moscow 109390, Russia
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Igor I. Miroshnichenko / Natalia V. Baymeeva / Valery V. Smirnov
  • National Research Center “Institute of Immunology” of Federal Medical and Biological Agency of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Elena A. Grishina
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kristina A. Ryzhikova
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Karin B. Mirzaev
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Dmitry D. Markov
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Valentin Y. Skryabin
  • Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nataliya E. Snalina
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Polina G. Nosikova / Ludmila M. Savchenko
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Evgeny A. Bryun
  • Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
  • Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow, Russian Federation
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2017-08-08 | DOI: https://doi.org/10.1515/dmpt-2017-0021

Abstract

Background:

Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder.

Methods:

The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-β-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-β-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS.

Results:

Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037].

Conclusions:

The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Keywords: adverse drug reactions; alcohol dependence; biotransformation; haloperidol; pharmacogenetics; therapeutic drug monitoring

References

  • 1.

    Acute alcohol withdrawal, National Institute for Health and Care Excellence, 2015, http://pathways.nice.org.uk/pathways/alcohol-use-disorders.

  • 2.

    Stewart S, Swain S; NICE; Royal College of Physicians, London. Assessment and management of alcohol dependence and withdrawal in the acute hospital. Clin Med 2012;12:266–71.CrossrefGoogle Scholar

  • 3.

    Fang J, McKay G, Song J, Remillrd A, Li X, Midha K. In vitro characterization of the metabolism of haloperidol using recombinant cytochrome P450 enzymes and human liver microsomes. Drug Metab Dispos 2001;29:1638–43.Google Scholar

  • 4.

    Ghosh C, Marchi N, Desai NK, Puvenna V, Hossain M. Cellular localization and functional significance of CYP3A4 in the human epileptic brain. Epilepsia 2011;52:562–71.Web of SciencePubMedCrossrefGoogle Scholar

  • 5.

    Langaee T, Hamadeh I, Chapman AB, Gums JG, Johnson JA. A novel simple method for determining CYP2D6 gene copy number and identifying allele(s) with duplication/multiplication. PLoS One 2015;10:e0113808.CrossrefWeb of SciencePubMedGoogle Scholar

  • 6.

    Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2012;91:321–6.CrossrefWeb of SciencePubMedGoogle Scholar

  • 7.

    Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369:23–37.PubMedCrossrefGoogle Scholar

  • 8.

    Nakamura A, Mihara K, Nemoto K. Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia. Ther Drug Monit 2014;36:815–8.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 9.

    Butwicka A, Krystyna S, Retka W, Wolańczyk T. Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency. Eur J Pediatr 2014;173:1639–42.CrossrefWeb of ScienceGoogle Scholar

  • 10.

    Gasso P, Papagianni K, Mas S. Relationship between CYP2D6 genotype and haloperidol pharmacokinetics and extrapyramidal symptoms in healthy volunteers. Pharmacogenomics 2013;14:1551–63.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 11.

    Sychev DA, Zastrozhin MS, Smirnov VV, Savchenko LM, Bryun EA, Guschina YuSh, et al. Association of isoenzyme CYP2D6 activity with efficacy and safety profile of haloperidol in patients with compulsive affection for alcohol. Bulletin of RSMU 2015;4:36–39.Google Scholar

  • 12.

    Sychev DA, Zastrozhin MS, Smirnov VV, Grishina EA, Savchenko LM, Bryun EA. The correlation between CYP2D6 isoenzyme activity and haloperidol efficacy and safety profile in patients with alcohol addiction during the exacerbation of the addiction. Pharmacogenomics Pers Med 2016;9:1–7.Web of ScienceGoogle Scholar

  • 13.

    Watanabe M, Tomonori T, Masako A, Hironori N, Masami T. Role of CYP3A in haloperidol N-dealkylation and pharmacokinetics in rats. Fundam Clin Pharmacol 1999;13:337–42.PubMedCrossrefGoogle Scholar

  • 14.

    Pan L, Belpaire FM. In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol. Eur J Clin Pharmacol 1999;55:599–604.CrossrefGoogle Scholar

  • 15.

    Drago A, Giegling I, Schäfer M, Hartmann AM, Möller HJ, De Ronchi D, et al. No association of a set of candidate genes on haloperidol side effects. PLoS One 2012;7:e44853.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 16.

    Van der Weide K, van der Weide J. The influence of the CYP3A4*22 polymorphism and CYP2D6 polymorphisms on serum concentrations of aripiprazole, haloperidol, pimozide, and risperidone in psychiatric patients. J Clin Psychopharmacol 2015;35:228–36.CrossrefWeb of SciencePubMedGoogle Scholar

  • 17.

    Ragia G, Dahl ML, Manolopoulos VG. Influence of CYP3A5 polymorphism on the pharmacokinetics of psychiatric drugs. Curr Drug Metab 2016;17:227–36.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 18.

    Zastrozhin MS, Smirnov VV, Sychev DA, Savchenko LM, Bryun EA, Matis OA. CYP3A4 activity and haloperidol effects in alcohol addicts. Int J Risk Saf Med 2015;27:23–4.CrossrefGoogle Scholar

  • 19.

    Zastrozhin MS, Smirnov VV, Sychev DA, Savchenko LM, Bryun EA, Guschina Y, et al. Study of carbamazepine influence on activity of cytochrome P-450 3A4 isoenzyme in patients with alcohol use disorder. Exp Clin Pharmacol 2016;10:18–22.Google Scholar

  • 20.

    Jiang XL, Shen HW, Yu AM. Pinoline may be used as a probe for CYP2D6 activity. Drug Metab Dispos 2009;37:443–6.Web of ScienceCrossrefPubMedGoogle Scholar

  • 21.

    Tay-Sontheimer J, Shireman LM, Beyer RP. Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. Pharmacogenomics 2014;15: 1947–62.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 22.

    Luo X, Li X, Hu Z, Cheng Z. Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism. Acta Pharmacologica Sinica 2009;30:1323–9.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 23.

    Mustafina OE, Tuktarova IA, Karimov DD, Somova RS, Nasibullin TR. CYP2D6, CYP3A5, and CYP3A4 gene polymorphism in Russian, Tatar, and Bashkir populations. Genetika 2015;51:109–19.PubMedGoogle Scholar

About the article

Received: 2017-06-13

Accepted: 2017-07-13

Published Online: 2017-08-08

Published in Print: 2017-09-26


Author contributions: DAS, MSZ1, IIM, LMS, and EAB analyzed the data. DAS, MSZ1, LMS, and EAB conceived and designed the study and supervised the work. DAS, MSZ1, IIM, NVB, EAG, LMS, and EAB wrote the reply to the reviewers and the revised manuscript. MSZ2 recruited the patients. EAG, KAR, KBM, DDM, NES, and ASS performed the genotyping of CYP2D6 and CYP3A5. VVS performed the phenotyping of CYP2D6 and CYP3A. IIM and NVB performed TDM. VS and PN performed translation. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved its submission.

Research funding: This work was supported by the Russian Science Foundation under the project 16-15-00227 “Fundamental research and exploratory research in priority areas of research.”

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Drug Metabolism and Personalized Therapy, Volume 32, Issue 3, Pages 129–136, ISSN (Online) 2363-8915, ISSN (Print) 2363-8907, DOI: https://doi.org/10.1515/dmpt-2017-0021.

Export Citation

©2017 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Mikhail S. Zastrozhin, Valery V. Smirnov, Alexander S. Sorokin, Elena A. Grishina, Kristina A. Ryzhikova, Valery V. Shipitsyn, Ludmila M. Savchenko, Oleg Z. Buzik, Sergey S. Koporov, Evgeny A. Bryun, and Dmitry A. Sychev
Annals of the Russian academy of medical sciences, 2019, Volume 74, Number 3, Page 185
[2]
M.S. Zastrozhin, V.Y. Skryabin, V.V. Smirnov, E.A. Grishina, K.A. Ryzhikova, E.M. Chumakov, E.A. Bryun, and D.A. Sychev
Canadian Journal of Physiology and Pharmacology, 2019, Volume 97, Number 8, Page 781
[3]
Mikhail S. Zastrozhin, Valery V. Smirnov, Alexander S. Sorokin, Elena A. Grishina, Kristina A. Ryzhikova, Inessa A. Bedina, Valery V. Shipitsyn, Ludmila M. Savchenko, Oleg Zh. Buzik, Sergey S. Koporov, Evgeny А. Bryun, and Dmitry A. Sychev
Annals of the Russian academy of medical sciences, 2018, Volume 73, Number 6, Page 411

Comments (0)

Please log in or register to comment.
Log in