The Association of CYP2D6*4 and POR*28 Polymorphisms on Mirtazapine Plasma Level in Subjects with Major Depressive Disorder and Anxiety Disorders

Author(s): Fezile Ozdemir, Emrah Dural, Nilay Sedes Baskak, Yağmur Kır, Bora Baskak, Halt S. Suzen*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 10 , 2020

Become EABM
Become Reviewer
Call for Editor


Aims and Objective: The plasma level of mirtazapine (MIR) varies between individuals primarily depending on the differences in metabolism during pharmacotherapy. CYP2D6 takes the role as a major enzyme in MIR metabolism and POR enzyme donates an electron to CYP2D6 for its activity. Single nucleotide polymorphisms in the genes encoding pharmacokinetic enzymes may cause changes in enzyme activity, leading to differences in metabolism of the drug. Our aim was to assess the influence of CYP2D6*4 and POR*28 polymorphisms on MIR plasma levels in Turkish psychiatric patients.

Materials and Methods: The association between genetic variations and plasma level of MIR was investigated on 54 patients. CYP2D6*4 and POR*28 polymorphisms were analysed using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and plasma MIR levels were measured using HPLC.

Results: Allele frequencies of CYP2D6*4 and POR*28 were 0.11 and 0.39, respectively in the study population. The results showed that CYP2D6*4 allele carriers have higher C/D MIR levels while POR*28 allele carriers have lower C/D MIR levels. Combined genotype analyses also revealed that individuals with CYP2D6*1/*1 - POR*28/*28 genotype have a statistically lower C/D MIR level (0.95 ng/ml/dose) when compared with individuals with CYP2D6*1/*1 - POR*1/*1 genotype (1.52 ng/ml/dose).

Conclusion: Our results indicate that CYP2D6*4 and POR*28 polymorphisms may have a potential in the explanation of differences in plasma levels in MIR treated psychiatric patients. A combination of these variations may be beneficial in increasing drug response and decreasing adverse drug reactions in MIR psychopharmacotherapy.

Keywords: Mirtazapine, CYP2D6*4, POR*28, plasma, HPLC, MIR psychopharmacotherapy.

GBD 2015 Disease and injury incidence and prevalence collaborators. global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet, 2016, 388(10053), 1789-1858.
Holm, K.J.; Markham, A.; Mirtazapine, A. Mirtazapine: a review of its use in major depression. Drugs, 1999, 57(4), 607-631.
[] [PMID: 10235695]
Hiemke, C.; Bergemann, N.; Clement, H.W.; Conca, A.; Deckert, J.; Domschke, K.; Eckermann, G.; Egberts, K.; Gerlach, M.; Greiner, C.; Gründer, G.; Haen, E.; Havemann-Reinecke, U.; Hefner, G.; Helmer, R.; Janssen, G.; Jaquenoud, E.; Laux, G.; Messer, T.; Mössner, R.; Müller, M.J.; Paulzen, M.; Pfuhlmann, B.; Riederer, P.; Saria, A.; Schoppek, B.; Schoretsanitis, G.; Schwarz, M.; Gracia, M.S.; Stegmann, B.; Steimer, W.; Stingl, J.C.; Uhr, M.; Ulrich, S.; Unterecker, S.; Waschgler, R.; Zernig, G.; Zurek, G.; Baumann, P. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018, 51(1-02), 9-62.
Furukawa, T.A.; Cipriani, A.; Cowen, P.J.; Leucht, S.; Egger, M.; Salanti, G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry, 2019, 6(7), 601-609.
[] [PMID: 31178367]
Hayashi, Y.; Watanabe, T.; Aoki, A.; Ishiguro, S.; Ueda, M.; Akiyama, K.; Kato, K.; Inoue, Y.; Tsuchimine, S.; Yasui-Furukori, N.; Shimoda, K. Factors affecting steady-state plasma concentrations of enantiomeric mirtazapine and its desmethylated metabolites in Japanese psychiatric patients. Pharmacopsychiatry, 2015, 48(7), 279-285.
[] [PMID: 26595747]
Anttila, S.A.; Leinonen, E.V.J. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev., 2001, 7(3), 249-264.
[] [PMID: 11607047]
Jaquenoud Sirot, E.; Harenberg, S.; Vandel, P.; Lima, C.A.; Perrenoud, P.; Kemmerling, K.; Zullino, D.F.; Hilleret, H.; Crettol, S.; Jonzier-Perey, M.; Golay, K.P.; Brocard, M.; Eap, C.B.; Baumann, P. Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression. J. Clin. Psychopharmacol., 2012, 32(5), 622-629.
[] [PMID: 22926595]
Störmer, E.; von Moltke, L.L.; Shader, R.I.; Greenblatt, D.J. Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab. Dispos., 2000, 28(10), 1168-1175.
[PMID: 10997935]
Gambi, F.; De Berardis, D.; Campanella, D.; Carano, A.; Sepede, G.; Salini, G.; Mezzano, D.; Cicconetti, A.; Penna, L.; Salerno, R.M.; Ferro, F.M. Mirtazapine treatment of generalized anxiety disorder: a fixed dose, open label study. J. Psychopharmacol. (Oxford), 2005, 19(5), 483-487.
[] [PMID: 16166185]
Leonard, S.D.; Karlamangla, A. Dose-dependent sedating and stimulating effects of mirtazapine. Proc UCLA Healthc, 2015, pp. 1-2.
Kirchheiner, J.; Henckel, H.B.; Meineke, I.; Roots, I.; Brockmöller, J. Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers. J. Clin. Psychopharmacol., 2004, 24(6), 647-652.
[] [PMID: 15538128]
Borobia, A.M.; Novalbos, J.; Guerra-López, P.; López-Rodríguez, R.; Tabares, B.; Rodríguez, V.; Abad-Santos, F.; Carcas, A.J. Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers. Pharmacol. Res., 2009, 59(6), 393-398.
[] [PMID: 19429471]
Zanger, U.M.; Raimundo, S.; Eichelbaum, M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch. Pharmacol., 2004, 369(1), 23-37.
[] [PMID: 14618296]
Saghafi, F.; Salehifar, E.; Janbabai, G.; Zaboli, E.; Hedayatizadeh-Omran, A.; Amjadi, O.; Moradi, S. CYP2D6*3 (A2549del), *4 (G1846A), *10 (C100T) and *17 (C1023T) genetic polymorphisms in Iranian breast cancer patients treated with adjuvant tamoxifen. Biomed. Rep., 2018, 9(5), 446-452.
[] [PMID: 30345040]
Fernández-Santander, A.; del Saz Sánchez, M.; Tejerina Gómez, A.; Bandrés Moya, F. CYP2D6*4 allele and breast cancer risk: is there any association? Clin. Transl. Oncol., 2012, 14(2), 157-159.
[] [PMID: 22301406]
Huang, N.; Agrawal, V.; Giacomini, K.M.; Miller, W.L. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc. Natl. Acad. Sci. USA, 2008, 105(5), 1733-1738.
[] [PMID: 18230729]
Sandee, D.; Morrissey, K.; Agrawal, V.; Tam, H.K.; Kramer, M.A.; Tracy, T.S.; Giacomini, K.M.; Miller, W.L. Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet. Genomics, 2010, 20(11), 677-686.
[] [PMID: 20940534]
Pandey, A.V.; Sproll, P. Pharmacogenomics of human P450 oxidoreductase. Front. Pharmacol., 2014, 5, 103.
[] [PMID: 24847272]
Zhang, H.F.; Li, Z.H.; Liu, J.Y.; Liu, T.T.; Wang, P.; Fang, Y.; Zhou, J.; Cui, M.Z.; Gao, N.; Tian, X.; Gao, J.; Wen, Q.; Jia, L.J.; Qiao, H.L. Correlation of cytochrome p450 oxidoreductase expression with the expression of 10 isoforms of cytochrome P450 in human liver. Drug Metab. Dispos., 2016, 44(8), 1193-1200.
[] [PMID: 27271371]
Hubbard, P.A.; Shen, A.L.; Paschke, R.; Kasper, C.B.; Kim, J.J.P. NADPH-cytochrome P450 oxidoreductase. Structural basis for hydride and electron transfer. J. Biol. Chem., 2001, 276(31), 29163-29170.
[] [PMID: 11371558]
Langman, L.; van Gelder, T.; van Schaik, R.N.H. Pharmacogenetics Aspects of Immunosuppressant Threapy.In: Personalized Immunosuppression in Transplantation Role of Biomarker Monitoring and Therapeutic Drug Monitoring; Oellerich, M.; Dasgupta, A., Eds.; Elsevier, 2016, pp. 109-124.
Flück, C.E.; Mullis, P.E.; Pandey, A.V. Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation. Mol. Cell. Endocrinol., 2009, 313(1-2), 17-22.
[] [PMID: 19744540]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed; , 2013.
Miller, S.A.; Dykes, D.D.; Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 1988, 16(3), 1215.
[] [PMID: 3344216]
Schur, B.C.; Bjerke, J.; Nuwayhid, N.; Wong, S.H. Genotyping of cytochrome P450 2D6*3 and *4 mutations using conventional PCR. Clin. Chim. Acta, 2001, 308(1-2), 25-31.
[] [PMID: 11412814]
Ozdemir, F.; Oz, M.D.; Suzen, H.S. A novel PCR-RFLP method for detection of por*28 polymorphism and its genotype/allele frequencies in a Turkish population. Curr. Drug Metab., 2019, 20(10), 845-851.
[] [PMID: 31518218]
Dural, E.; Baskak, N.S.; Ozcan, H.; Kır, Y.; Baskak, B.; Suzen, H.S. Determination of mirtazapine and desmethyl mirtazapine in human plasma by a new validated HPLC ultraviolet method with a simple and reliable extraction method: Application to therapeutic drug monitoring study by 62 real patient plasma. Iran. J. Pharm., 2020, 19(1), 18-30.
Zastrozhin, M.S.; Skryabin, V.Y.; Smirnov, V.V.; Grishina, E.A.; Ryzhikova, K.A.; Chumakov, E.M.; Bryun, E.A.; Sychev, D.A. Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder. Can. J. Physiol. Pharmacol., 2019, 97(8), 781-785.
[] [PMID: 31100205]
Grasmäder, K.; Verwohlt, P.L.; Rietschel, M.; Dragicevic, A.; Müller, M.; Hiemke, C.; Freymann, N.; Zobel, A.; Maier, W.; Rao, M.L. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur. J. Clin. Pharmacol., 2004, 60(5), 329-336.
[] [PMID: 15168101]
de Jonge, H.; Metalidis, C.; Naesens, M.; Lambrechts, D.; Kuypers, D.R.J. The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics, 2011, 12(9), 1281-1291.
[] [PMID: 21770725]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [1032 - 1040]
Pages: 9
DOI: 10.2174/1386207323666200402081512
Price: $65

Article Metrics

PDF: 26