1. bookVolume 39 (2018): Issue 2-3 (December 2018)
Journal Details
License
Format
Journal
eISSN
1857-8985
ISSN
1857-9345
First Published
08 Sep 2014
Publication timeframe
2 times per year
Languages
English
access type Open Access

Evaluation of Correlation Between the Pharmacogenetic Profiles of Risperidone Treated Psychiatry Patients with Plasma and Urine Concentration of Risperidone and its Active Moiety 9-OH Risperidone Determined with Optimized Bioanalytical LC Method

Journal Details
License
Format
Journal
eISSN
1857-8985
ISSN
1857-9345
First Published
08 Sep 2014
Publication timeframe
2 times per year
Languages
English
Abstract

Atypical antipsychotic risperidone is widely used first-line monotherapy in schizophrenia and combined therapy in bipolar disorders. Therapeutic plasma concentrations of risperidone and its active moiety are directly influenced by genetic variations in metabolic CYP450 enzymes (CYP2D6 and CYP3A4/5) and transporter (ABCB1) protein and additional environmental factors. Since active metabolite 9-OH risperidone has a greater percentage of the pharmacologically active fraction and is equipotent to the parent drug risperidone, it is assumed that it contributes significantly to therapeutic and adverse effects.

Unpredictable dose/concentration ratio, narrow therapeutic index, number of interactions, along with serious adverse reactions (ADR), raises the need for individualization of risperidone treatment and establishing of good therapeutic regime using TDM.

A simple and reliable validated bioanalytical liquide-liquide extraction HPLC/UV method was applied for the simultaneous determination of risperidone and its active metabolite, 9-OH risperidone, in human plasma and urine of 52 hospitalized schizophrenia/bipolar disorder patients treated with risperidone as monotherapy and in polytherapy. All the patients were previously genotyped for CYP2D6 (EM=30, EM/IM=14, IM=4 IM/PM=1 and PM=3) and ABCB1 using Real-Time PCR methods with TaqMan SNP genotyping suitable assays according to the guidelines of the manufacturer (Life Technologies, USA).The influence of CYP2D6 phenotype on metabolic ratio MR (Ris/9-OHRis) in plasma (p=0.012) and in urine (p=0.048) was confirmed. Statistically significant correlation (R2=55.53%, Rho=0.844, p<0,0001) for MR in both plasma and urine indicates that urine may be utilized as appropriate media for initial CYP2D6 phenotype identification and selection of patients on risperidone treatment with high risk for ADR.

Keywords

1. Gardner ER, Figg WD, Sparreboom A., Pharmacogenomics of the Human ATP-Binding Cassette Transporter ABCG2.Current Pharmacogenomics 11/2006; 4(4): 331–344.10.2174/157016006778992778Search in Google Scholar

2. Aichhorn W, Weiss U, Marksteiner J, Kemmler G, Walch T, Zernig G, Stelzig-Schoeler R, Stuppaeck C, Geretsegger C. Influence of age and gender on risperidone plasma concentrations. J Psychopharmacol. 2005 Jul; 19(4): 395–401. Laysen JE et al., 1988–9.10.1177/026988110505330615982995Open DOISearch in Google Scholar

3. Rafaniello C, Sessa M, Bernardi FF, Pozzi M, Cheli S, Cattaneo D, Baldelli S, Molteni M, Bernardini R, Rossi F, Clementi E, Bravaccio C, Radice S, Capuano A. The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions. Pharmacogenomics J. 2018 May 22; 18(3): 422–430.10.1038/tpj.2017.38Open DOISearch in Google Scholar

4. Vandenberghe F, Guidi M, Choong E, von Gunten A, Conus P, Csajka C, Eap CB. Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort. Clin Pharmacokinet. 2015 Dec; 54(12): 1259–72.10.1007/s40262-015-0289-8Search in Google Scholar

5. Bork JA, Rogers T, Wedlund PJ, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. J Clin Psychiatry. 1999 Jul; 60(7): 469–76.10.4088/JCP.v60n0709Search in Google Scholar

6. de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005 Jan; 66(1): 15–27.10.4088/JCP.v66n0103Search in Google Scholar

7. de Leon J, Sandson NB, Cozza KL. A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part II. Psychosomatics. 2008 Jul-Aug; 49(4): 347–61.10.1176/appi.psy.49.4.347Open DOISearch in Google Scholar

8. Wang JS, DeVane CL, Gibson BB, Donovan JL, Markowitz JS, Zhu HJ. Population pharmacokinetic analysis of drug-drug interactions among risperidone, bupropion, and sertraline in CF1 mice. Psychopharmacology (Berl). 2006 Jan; 183(4): 490–9.10.1007/s00213-005-0209-ySearch in Google Scholar

9. Baumann P, Hiemke C, Ulrich S, Gaertner I, Rao ML, Eckermann G, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Riederer P, Zernig G. Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline. Ther Drug Monit. 200410.1097/00007691-200404000-0001415228159Open DOISearch in Google Scholar

10. Seto K, Dumontet J, Ensom MH.Risperidone in schizophrenia: is there a role for therapeutic drug monitoring? Ther Drug Monit. 2011 Jun; 33(3): 275–83.10.1097/FTD.0b013e3182126d83Search in Google Scholar

11. Jovanović N, Božina N, Lovrić M, Medved V, Jakovljević M, Peleš AM. The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone. Eur J Clin Pharmacol. 2010 Nov; 66(11): 1109–17.10.1007/s00228-010-0850-1Search in Google Scholar

12. Naumovska Z, Brezovska K, Tonic-Ribarska J, Kapedanovska Nestorovska A, Sterjev Z, Grozdanova A, Filipce A, Suturkova Lj. Optimization of bioanalytical LC method for simultaneous determination of risperidone and its active metabolite 9-OH risperidone in human plasma and urine. IOSR Journal of Pharmacy www.iosrphr.org (e)-ISSN: 2250-3013, (p) - ISSN: 2319 – 4219 Volume 7, Issue 12 Version. 1 (December 2017), PP. 54–64.Search in Google Scholar

13. Cabovska B, Cox SL, Vinks AA. Determination of risperidone and enantiomers of 9-hydroxyrisperidone in plasma by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 1; 852(1-2): 497–504. Epub 200710.1016/j.jchromb.2007.02.007Search in Google Scholar

14. Foroutan, S.M., Zarghi, A., Shafaati A. (2006) Foroutan, S.M., Zarghi, A., Shafaati A. Rapid high performance liquid chromatographic determina tion of risperidone in human plasma. Iranian Journal of Pharmaceutical Research. (2006) 1, 37–40.Search in Google Scholar

15. Dean L. Clozapine Therapy and CYP2D6, CYP1A2, and CYP3A4 Genotypes. 2016 Jun 8. In: Pratt V, McLeod H, Rubinstein W, Dean L, Kattman B, Malheiro A, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from http://www.ncbi.nlm.nih.gov/books/NBK367795/PubMed PMID: 28520368.Search in Google Scholar

16. Mannheimer B, Holm J, Koukel L, Bertilsson L, Osby U, Eliasson E. Risperidone metabolic ratio as a biomarker of individual CYP2D6 genotype in schizophrenic patients. Eur J Clin Pharmacol. 2014 Jun; 70(6): 695–9.10.1007/s00228-014-1664-3Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo