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Current Pharmacogenomics and Personalized Medicine


ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Research Article

Differences in MDR1 (C3435T), CYP2D6, and CYP1A2 Genotype Frequencies between Patients with Treatment Failure to Antipsychotics and Healthy Russian Population

Author(s): Tatiana Zhiganova *, Radkova Eugenia, Sergeeva Tatiana and Volovnikova Viktoriia

Volume 17, Issue 1, 2020

Page: [55 - 63] Pages: 9

DOI: 10.2174/1875692117666190724141831


Background: Personalized approach is one of the options to overcome treatment failure in psychiatry and increase the efficacy of antipsychotic treatment for an individual patient by using genetic tests.

Objective: The aim of this study was to investigate the frequency of MDR1 (C3435T), CYP2D6, CYP2C19, and CYP1A2 genotypes in psychiatric patients with treatment failure to antipsychotics to compare the results with those published for the Russian population.

Methods: A total number of 52 patients attending a psychiatry outpatient clinic were included in the study. All patients required changing the therapy with antipsychotics due to treatment failure.

Results: We revealed the higher frequency of Т/Т MDR1 (C3435T) homozygotes among study patients as compared with the Russian healthy population. For CYP1A2, the higher frequency of normal metabolizers (*1A/*1A) and lower frequency of slow metabolizers (*1F/*1F) were observed. No difference was found for intermediate metabolizers (*1A/*1F) and one patient had *1A/*1C genotype with decreased activity. For the majority of CYP2D6 genotypes, the observed frequencies were similar to those reported for the Russian healthy population except for CYP2D6 *3/*4 (slow metabolizers), for which higher frequency among study patients was found. The frequencies of CYP2С19 genotypes were comparable to the Russian population, however, no slow metabolizers (*2/*2, *2/*3, *3/*3 genotypes) were identified.

Conclusion: Psychiatric patients with treatment failure to antipsychotics demonstrated a high frequency of T/T MDR1 (C3435T) and CYP2D6 *3/*4 genotypes coding inactive proteins. The frequency of CYP1A2 wild type genotype *A/*A was higher with a simultaneous decrease in the frequency of *F/*F genotype compared with the healthy Russian population. Further studies of MDR1 (C3435T) genotype as well as CYP2D6, CYP2C19, and CYP1A2 genotypes frequency should be conducted in patients with treatment failure to antipsychotics.

Keywords: Pharmacogenetics, antipsychotics, MDR1, cytochrome system, CYP2D6, CYP2C19, CYP1A2.

Graphical Abstract
Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry. 11th ed. London: Wiley-Backwell 2012.
Tannenbaum C, Sheehan NL. Understanding and preventing drug-drug and drug-gene interactions. Expert Rev Clin Pharmacol 2014; 7(4): 533-44.
[] [PMID: 24745854]
Thomas L, Kessler D, Campbell J, et al. Prevalence of treatment-resistant depression in primary care: cross-sectional data. Br J Gen Pract 2013; 63(617): e852-8.
[] [PMID: 24351501]
Eap CB. Personalized prescribing: a new medical model for clinical implementation of psychotropic drugs. Dialogues Clin Neurosci 2016; 18(3): 313-22.
[PMID: 27757065]
Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9(5): 442-73.
[] [PMID: 15037866]
Woolfolk R, Lesley A. Mental Disorders – Theoretical and Empirical Perspectives.. 2013. books/mental-disorders-theoretical-and-empirical-perspec-tives [Accessed February 27, 2019].
de Leon J, Arranz MJ, Ruaño G. Pharmacogenetic testing in psychiatry: a review of features and clinical realities. Clin Lab Med 2008; 28(4): 599-617.
[] [PMID: 19059065]
Mrazek DA. Psychiatric Pharmacogenomics. New York: Oxford University Press 2010.
Durham D, Thirumaran R. Psychiatric Pharmacogenetics: from concepts to cases. New York: Fortis Caliga Academic Press 2017.
Brandl EJ, Kennedy JL, Müller DJ. Pharmacogenetics of antipsychotics. Can J Psychiatry 2014; 59(2): 76-88.
[] [PMID: 24881126]
Manolio TA, Chisholm RL, Ozenberger B, et al. Implementing genomic medicine in the clinic: the future is here. Genet Med 2013; 15(4): 258-67.
[] [PMID: 23306799]
Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005; 5(1): 6-13.
[] [PMID: 15492763]
US Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling drugs/science-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
Eum S, Lee AM, Bishop JR. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues Clin Neurosci 2016; 18(3): 323-37.
[PMID: 27757066]
Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther 2015; 98(2): 127-34.
[] [PMID: 25974703]
Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003; 59(4): 303-12.
[] [PMID: 12879168]
Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001; 69(3): 169-74.
[] [PMID: 11240981]
Pechandová K, Buzková H, Slanař O, Perlík F. Polymorphisms of the MDR1 gene in the Czech population. Folia Biol (Praha) 2006; 52(6): 184-9.
[PMID: 17184596]
Milojkovic M, Stojnev S, Jovanovic I, Ljubisavljevic S, Stefanovic V, Sunder-Plassman R. Frequency of the C1236T, G2677T/A and C3435T MDR1 gene polymorphisms in the Serbian population. Pharmacol Rep 2011; 63(3): 808-14.
[] [PMID: 21857092]
Korytina G, Kochetova O, Akhmadishina L, Viktorova E, Victorova T. Polymorphisms of cytochrome p450 genes in three ethnic groups from Russia. Balkan Med J 2012; 29(3): 252-60.
[] [PMID: 25207010]
Gra O, Mityaeva O, Berdichevets I, et al. Microarray-based detection of CYP1A1, CYP2C9, CYP2C19, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, NAT2, HLA-DQA1, and AB0 allele frequencies in native Russians. Genet Test Mol Biomarkers 2010; 14(3): 329-42.
[] [PMID: 20373852]
Sychev DA, Denisenko NP, Sizova ZM, Grachev AV, Velikolug KA. The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors. Pharm Genomics Pers Med 2015; 8: 111-4.
[PMID: 26109874]
Kastelic M, Koprivsek J, Plesnicar BK, et al. MDR1 gene polymorphisms and response to acute risperidone treatment. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(2): 387-92.
[] [PMID: 20060871]
El Ela AA, Härtter S, Schmitt U, Hiemke C, Spahn-Langguth H, Langguth P. Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol 2004; 56(8): 967-75.
[] [PMID: 15285840]
Zhu HJ, Wang JS, Markowitz JS, Donovan JL, Gibson BB, DeVane CL. Risperidone and paliperidone inhibit p-glycoprotein activity in vitro. Neuropsychopharmacology 2007; 32(4): 757-64.
[] [PMID: 16936711]
Boulton DW, DeVane CL, Liston HL, Markowitz JS. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci 2002; 71(2): 163-9.
[] [PMID: 12031686]
Moons T, de Roo M, Claes S, Dom G. Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics 2011; 12(8): 1193-211.
[] [PMID: 21843066]
Zheng M, Zhang H, Dill DL, et al. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans. PLoS Med 2015; 12(2)e1001782
[] [PMID: 25647612]
Wang JS, Zhu HJ, Donovan JL, et al. Aripiprazole brain concentration is altered in P-glycoprotein deficient mice. Schizophr Res 2009; 110(1-3): 90-4.
[] [PMID: 19239981]
Nagasaka Y, Sano T, Oda K, Kawamura A, Usui T. Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole. Xenobiotica 2014; 44(10): 926-32.
[] [PMID: 24666334]
Ejsing TB, Pedersen AD, Linnet K. P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments. Hum Psychopharmacol 2005; 20(7): 493-500.
[] [PMID: 16118767]
Wang JS, Taylor R, Ruan Y, Donovan JL, Markowitz JS, Lindsay De Vane C. Olanzapine penetration into brain is greater in transgenic Abcb1a P-glycoprotein-deficient mice than FVB1 (wild-type) animals. Neuropsychopharmacology 2004; 29(3): 551-7.
[] [PMID: 14702023]
Schmitt U, Kirschbaum KM, Poller B, et al. In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo nicely reflected by pharmacodynamic but less by pharmacokinetic changes. Pharmacol Biochem Behav 2012; 102(2): 312-20.
[] [PMID: 22525746]
Doran A, Obach RS, Smith BJ, et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 2005; 33(1): 165-74.
[] [PMID: 15502009]
Kuzman MR, Medved V, Bozina N, Hotujac L, Sain I, Bilusic H. The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. Psychiatry Res 2008; 160(3): 308-15.
[] [PMID: 18718676]
Jaquenoud Sirot E, Knezevic B, Morena GP, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol 2009; 29(4): 319-26.
[] [PMID: 19593168]
González-Vacarezza N, Dorado P, Peñas-Lledó EM, Fariñas H, Estévez-Carrizo FE, Llerena A. MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers. Drug Metabol Drug Interact 2013; 28(3): 163-6.
[] [PMID: 23740681]
Lin YC, Ellingrod VL, Bishop JR, Miller DD. The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia. Ther Drug Monit 2006; 28(5): 668-72.
[] [PMID: 17038883]
Bozina N, Granić P, Lalić Z, Tramisak I, Lovrić M, Stavljenić-Rukavina A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003; 44(4): 425-8.
[PMID: 12950145]
Rideg O, Háber A, Botz L, et al. Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. Cell Biochem Funct 2011; 29(7): 562-8.
[] [PMID: 21826689]
Correia C, Santos P, Coutinho AM, Vicente AM. Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample. Cell Biochem Funct 2009; 27(4): 251-5.
[] [PMID: 19405050]
Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med 2017; 19(1): 69-76.
[] [PMID: 27388693]
Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007; 17(2): 93-101.
[PMID: 17301689]
Patwardhan B, Chaguturu R. Innovative Approaches in Drug Discovery Ethnopharmacology, System Biology and Holistic Targeting. Academic Press 2017.
Zabrocka M, Woszczek G, Borowiec M, Rabe-Jabłońska J, Kowalski ML. [CYP2D6 gene polymorphism in psychiatric patients resistant to standard pharmacotherapy]. Psychiatr Pol 1999; 33(1): 91-100.
[PMID: 10786218]
Thümmler S, Dor E, David R, et al. Pharmacoresistant Severe Mental Health Disorders in Children and Adolescents: Functional Abnormalities of Cytochrome P450 2D6. Front Psychiatry 2018; 9: 2.
[] [PMID: 29472872]
van de Bilt MT, Prado CM, Ojopi EP, et al. Cytochrome P450 genotypes are not associated with refractoriness to antipsychotic treatment. Schizophr Res 2015; 168(1-2): 587-8.
[] [PMID: 26298540]

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