Preliminary Clinical Investigation of Combinatorial Pharmacogenomic Testing for the Optimized Treatment of Depression: A Randomized Single-Blind Study.

Front Neurosci. 2019;13:960

Authors: Shan X, Zhao W, Qiu Y, Wu H, Chen J, Fang Y, Guo W, Li L

Abstract
This study aims to explore the potential benefits of antidepressant drugs related to metabolic enzyme and drug-targeted genes, identify the optimal treatment of major depression, and provide a reference for individualized medication selection. A prospective randomized single-blind investigation was conducted for 8 weeks. A pharmacogenomic-based interpretive report was provided to the treating physician in the guided group. Patients in this group were informed that their medication selection was directed by DNA testing. In the unguided group, treatment was provided based on the clinical experience of the physician without the guidance of pharmacogenomic testing. Pharmacogenomic-based interpretive report was not provided to these patients until treatment completion. The 17-item Hamilton depression scale (HAMD-17), Hamilton anxiety scale, and treatment emergent symptom scale were used to assess the clinical efficacy and side effects at baseline and after 2, 4, and 8 weeks of treatment. Among the 80 initially enrolled patients with depression, 71 participated in the full data analysis sets and were designated into guided (31) and unguided (40) groups, respectively. No significant difference (P > 0.05) in HAMD-17 total scores, response and remission rates was found between the guided and unguided groups at the end of the treatment. The incidence rate of adverse reaction was 55.56% in guided group and 57.89% in the unguided group. Our study suggested that pharmacogenomic testing might not considerably improve the clinical efficiency and safety for the guided group.

PMID: 31572113 [PubMed]

Association of IL-10-1082A/G polymorphism with cardiovascular disease risk: Evidence from a case-control study to an updated meta-analysis.

Mol Genet Genomic Med. 2019 Sep 30;:e888

Authors: Lu S, Zhong J, Huang K, Zhou H

Abstract
BACKGROUND: Previous studies have generated controversial results about the association of interleukin 10 (IL-10) gene polymorphisms (-1082G/A) in the progression of cardiovascular disease (CVD). Therefore, this study processed a systemic meta-analysis to verify this association.
METHODS: The publication studies on the IL-10 (-1082G/A) polymorphism and CVDs risk were obtained by searching PubMed and Embase databases. We analyzed the genotype data for meta-analysis. The results were evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). Meanwhile, our meta-analysis was also performed sensitivity analyses, heterogeneity test, and identification of publication bias.
RESULTS: The present meta-analysis suggested that the risk with allele G is lower than with allele A for CVD. The G allele of IL-10 (-1082) could increase the risk of CVDs in the 31 case-control studies for all genetic models. (OR = 1.10, 95% CI: 1.04-1.15 for the allele model A vs. G; OR = 0.87, 95% CI: 0.72-1.04 for the dominant model GG+AG vs. AA; OR = 1.03, 95% CI: 1.02-1.05 for the recessive model GG vs. AG + AA; OR = 1.06, 95% CI = 1.03-1.10 for the homozygote comparison model GG vs. AA; and OR = 0.88, 95% CI = 0.73-1.06 for the heterozygote comparison model AG vs. AA).
CONCLUSIONS: In genetic models, the association between the IL-10 (-1082G/A) polymorphism and CVDs risk was significant. This meta-analysis proposes that the IL-10 (-1082G/A) polymorphism may serve as a risk factor for CVDs.

PMID: 31571432 [PubMed - as supplied by publisher]

Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia.

Neurosci Bull. 2019 Sep 30;:

Authors: Zhao L, Wang H, Zhang Y, Wei J, Ni P, Ren H, Li G, Wang Q, Reynolds GP, Yue W, Deng W, Yan H, Tan L, Chen Q, Yang G, Lu T, Wang L, Zhang F, Yang J, Li K, Lv L, Tan Q, Li Y, Yu H, Zhang H, Ma X, Yang F, Li L, Wang C, Wang H, Li X, Guo W, Hu X, Tian Y, Ma X, Coid J, Zhang D, Chen C, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

PMID: 31571100 [PubMed - as supplied by publisher]

Age as a Predictor of Treatment Outcome in Metastatic Testicular Germ Cell Tumors.

Anticancer Res. 2019 Oct;39(10):5589-5596

Authors: Terbuch A, Posch F, Bauernhofer T, Pichler M, Peinsith H, Szkandera J, Riedl J, Hutterer GC, Pummer K, Partl R, Kapp KS, Stöger H, Stotz M, Gerger A

Abstract
BACKGROUND/AIM: To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT).
PATIENTS AND METHODS: Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed.
RESULTS: Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022).
CONCLUSION: Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.

PMID: 31570454 [PubMed - in process]

On the Marketing and Use of Pharmacogenetic Tests for Psychiatric Treatment.

JAMA Psychiatry. 2018 08 01;75(8):769-770

Authors: Zubenko GS, Sommer BR, Cohen BM

PMID: 29799933 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/09/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Effect of Genetic and Non-genetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure.

Clin Transl Sci. 2019 Sep 27;:

Authors: Sarhan NM, Shahin MH, El Rouby NM, El-Wakeel LM, Solayman MH, Langaee T, Khorshid H, Schaalan MF, Sabri NA, Cavallari LH

Abstract
This prospective cohort study evaluated the association between renin-angiotensin-aldosterone-system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC=16%, CT=48%, and TT=36%. Frequencies for CYP11B2 rs1799998 were: TT=33%, TC=50%, and CC=17%. After six months of spironolactone treatment, change in left ventricular ejection fraction (LVEF) differed by both AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; p=2.1E-26) and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; p=0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (p=0.001), 63% of variability in serum potassium increase (p=2.25E-08), and 39% of the variability in improvement in quality of life (p=2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.

PMID: 31560448 [PubMed - as supplied by publisher]

APOE polymorphism is associated with blood lipid and serum uric acid metabolism in hypertension or coronary heart disease in a Chinese population.

Pharmacogenomics. 2019 Sep;20(14):1021-1031

Authors: Wang C, Yan W, Wang H, Zhu J, Chen H

Abstract
Aim: To explore the association of APOE polymorphism (rs7412:526C>T and rs429358:388T>C) with glucose, lipid and serum uric acid (UA) metabolism in patients with hypertension or coronary heart disease (CHD). Methods: A total of 544 patients with hypertension or CHD were selected for this study from March 2017 to January 2018. According to the APOE genotypes (excluding the E2/E4 genotype), the subjects were divided into three groups (E2/E2+E2/E3 genotypes, E3/E3 genotype [the wild-type] and E3/E4+E4/E4 genotypes) and the difference of metabolism among the three groups was compared. Results: There were significant differences in total cholesterol (TC), triglycerides, low-density lipoprotein (LDL), high-density lipoprotein and serum UA levels among the three groups. Compared with APOE E3 homozygote, APOE E4 carriers possessed higher TC, triglycerides and LDL levels, whereas APOE E2 carriers had higher high-density lipoprotein level, lower TC and LDL levels. Furthermore, multivariate logistic regression analysis found that setting E3/E3 genotype as the reference group, the carriers of APOE E4 allele (E3/E4+E4/E4 genotypes) were significantly related to hypertriglyceridemia, and APOE E2 allele (E2/E2+E2/E3 genotypes) was significantly correlated with hyperuricemia. Conclusion: APOE polymorphism was associated with blood lipid and serum UA metabolism in patients with hypertension or CHD. Compared with APOE E3 homozygote, APOE E4 allele was related to elevated triglycerides, and APOE E2 allele was correlated with increased serum UA level.

PMID: 31559922 [PubMed - in process]

Nanopore sequencing of the pharmacogene CYP2D6 allows simultaneous haplotyping and detection of duplications.

Pharmacogenomics. 2019 Sep;20(14):1033-1047

Authors: Liau Y, Maggo S, Miller AL, Pearson JF, Kennedy MA, Cree SL

Abstract
Aim: Long read sequencing offers the promise of overcoming some of the challenges in accurate genotyping of complex genes, along with the advantage of straightforward variant phasing. We have established methods for sequencing and haplotyping of the whole CYP2D6 gene using nanopore sequencing. Materials and methods: 32 samples covering various haplotypes including gene duplication were sequenced on the GridION platform. Results: Haplotypes of 52 alleles matched accurately to known star (*) allele subvariants, with the remaining 12 being assigned as new alleles, or new subvariants of known alleles. Duplicated alleles could be detected by analyzing the allelic balance. Conclusion: Nanopore sequencing of CYP2D6 offers a high throughput method for accurate haplotyping, detection of new variants and determination of duplicated alleles.

PMID: 31559921 [PubMed - in process]

Integration of machine learning and pharmacogenomic biomarkers for predicting response to antidepressant treatment: can computational intelligence be used to augment clinical assessments?

Pharmacogenomics. 2019 Sep;20(14):983-988

Authors: Athreya AP, Iyer R, Wang L, Weinshilboum RM, Bobo WV

PMID: 31559920 [PubMed - in process]

Characterizing the pharmacogenome using molecular inversion probes for targeted next-generation sequencing.

Pharmacogenomics. 2019 Sep;20(14):1005-1020

Authors: Suzuki O, Dong OM, Howard RM, Wiltshire T

Abstract
Aim: This study assesses the technical performance and cost of a targeted next-generation sequencing (NGS) multigene pharmacogenetic (PGx) test. Materials & methods: A genetic test was developed for 21 PGx genes using molecular inversion probes to generate library fragments for NGS. Performance of this test was assessed using 53 unique reference control cell lines from the Genetic Testing Reference Materials Coordination Program (GeT-RM). Results: 93.7% of variants were successfully called and the repeatability rate was 99.9%. Reference calls were available for 78.4% of diplotype calls resulting from PGx testing, and concordance for the test was 85.7%. Cost per sample was $32-$56. Conclusion: A targeted NGS assay using molecular inversion probe technology is able to characterize the pharmacogenome efficiently.

PMID: 31559919 [PubMed - in process]

Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.

Pharmacogenomics. 2019 Sep;20(14):989-1003

Authors: Sadhasivam S, Brandom BW, Henker RA, McAuliffe JJ

Abstract
Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

PMID: 31559918 [PubMed - in process]

miRNAs in drug response variability: potential utility as biomarkers for personalized medicine.

Pharmacogenomics. 2019 Sep;20(14):1049-1059

Authors: Latini A, Borgiani P, Novelli G, Ciccacci C

Abstract
MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. Almost all physiological conditions are probably modulated by miRNAs, including pharmacological response. Indeed, acting on the regulation of numerous genes involved in the pharmacokinetics and pharmacodynamics of drugs, differences in the levels of circulating miRNAs or genetic variants in the sequences of the miRNA genes can contribute to interindividual variability in drug response, both in terms of toxicity and efficacy. For their stability in body fluids and the easy availability and accurate quantification, miRNAs could be ideal biomarkers of individual response to drugs. This review aims to give an overview on the available studies that have investigated the relationship between miRNAs and response to drugs in different classes of diseases and considered their possible clinical application as therapy response predictive biomarkers. A comprehensive search was conducted from the international web database PubMed. We included papers that investigated the relationship between miRNAs and response to drugs, published before January 2019.

PMID: 31559917 [PubMed - in process]

Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinson's Disease.

Planta Med. 2019 Sep 26;:

Authors: Cacabelos R, Carrera I, Alejo R, Fernández-Novoa L, Cacabelos P, Corzo L, Rodríguez S, Alcaraz M, Tellado I, Cacabelos N, Pego R, Carril JC

Abstract
Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinson's disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 - 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.

PMID: 31559607 [PubMed - as supplied by publisher]

Polymorphisms in miRNAs Gene (146a, 149, 196a) and Susceptibility to ARV-associated Hepatotoxicity.

Curr Genomics. 2019 Feb;20(2):134-150

Authors: Singh HO, Jadhav S, Samani D, Dhole TN

Abstract
Background: Micro RNAs act as a regulatory layer for pharmacogenomics-related gene ex-pression. It could play a role in the efficacy and toxicity of the drug. The SNPs in miRNA genes are linked with different functional consequences.
Methods: Hence, we examined the miR (146a G/C, 149C/T, and 196aC/T) polymorphisms in 34 pa-tients with hepatotoxicity, 123 patients without hepatotoxicity, and 155 healthy controls using a PCR-RFLP method.
Results: In patients with hepatotoxicity, miR196aCT genotype and combined genotype GCT showed a risk for hepatotoxicity severity with borderline significance (OR=2.08, P=0.07; OR=2.88, P=0.06). While comparing between patients with hepatotoxicity and healthy controls, the combined genotypes CCC and GCT have shown a susceptibility to hepatotoxicity severity (OR=2.89, P=0.05; OR=2.60, P=0.09). The miR196TT genotype was associated with the individuals of advanced HIV disease stage (OR=3.68, P=0.04). In HIV patients who consumed alcohol and did not have hepatotoxicity, the miR 196aCT genotype showed susceptibility to acquisition of hepatotoxicity with borderline significance (OR=2.36, P=0.06).
Discussion: The miR149TT and 196aTT genotypes showed a risk of acquisition of hepatotoxicity to nevirapine usage among HIV patients without hepatotoxicity (OR=4.19, P=0.07; OR=1.97, P=0.84). In HIV patients with and without hepatotoxicity, the miR 196aCT genotype showed a risk of acquisition of hepatotoxicity and its severity to the combined use of alcohol and nevirapine, respectively (OR=14.18, P=0.08; OR=2.29, P=0.08). In multivariate logistic regression, taking nevirapine, 196aCT genotype had an independent risk factor for hepatotoxicity severity (OR=5.98, P=0.005; OR=2.38, P=0.05).Conclusion: In conclusion, miR196aC/T polymorphism and combined genotypes GCT and CCC may facilitate the risk for acquisition of hepatotoxicity and its severity.

PMID: 31555064 [PubMed]

Pharmacogenomics and Placebo Response in a Randomized Clinical Trial in Asthma.

Clin Pharmacol Ther. 2019 Sep 26;:

Authors: Wang RS, Croteau-Chonka DC, Silverman EK, Loscalzo J, Weiss ST, Hall KT

Abstract
Genetic variation may differentially modify drug and placebo treatment effects in randomized trials (RCTs). In asthma, although lung function and asthma control improvements are commonplace with placebo, pharmacogenomics of placebo versus drug response remains unexamined. In a GWAS of subjective and objective outcomes with placebo treatment in Childhood Asthma Management Program (CAMP) of nedocromil/budesonide versus placebo (N=604), effect estimates for lead SNPs were compared across arms. The coughing/wheezing lead SNP, rs2392165 (β=0.94; P=1.10E-07) mapped to BBS9, a gene implicated in lung development which contains a lung function expression quantitative trait locus (eQTL). The effect was attenuated with budesonide (Pinteraction =1.48E-07), but not nedocromil (Pinteraction =0.06). The lead FVC SNP, rs12930749 (β=-5.80; P=1.47E-06), mapped to KIAA0556, a locus genome-wide associated with respiratory diseases. The rs12930749 effect was attenuated with budesonide (Pinteraction =1.32E-02) and nedocromil (Pinteraction =1.09E-02). Pharmacogenomic analysis revealed differential effects with placebo and drug treatment that could potentially guide precision drug development in asthma.

PMID: 31557306 [PubMed - as supplied by publisher]

The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria.

Sci Adv. 2019 Sep;5(9):eaaw6127

Authors: Wang P, Sachar M, Lu J, Shehu AI, Zhu J, Chen J, Liu K, Anderson KE, Xie W, Gonzalez FJ, Klaassen CD, Ma X

Abstract
Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.

PMID: 31555729 [PubMed - in process]

Potential Regulation of UGT2B10 and UGT2B7 by miR-485-5p in human liver.

Mol Pharmacol. 2019 Sep 25;:

Authors: Sutliff AK, Shi J, Watson CJW, Hunt M, Chen G, Zhu HJ, Lazarus P

Abstract
The UDP-glucuronosyltransferase (UGT) family of enzymes are important in the metabolic elimination of a variety of endogenous compounds such as bile acids, steroids, and fat-soluble vitamins, as well as exogenous compounds including many pharmaceuticals. The UGT2B subfamily are the predominant isoforms expressed in human liver. The identification of novel mechanisms including post-transcriptional regulation by microRNA (miRNA) contribute to inter-individual variability in UGT2B expression and are crucial components in predicting patient drug response. In the present study, a high resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was employed to measure UGT2B protein levels in a panel of human liver microsomal samples. Concurrent in silico analysis identified eight candidate miRNA as potential regulators of UGT2B enzymes. Comparison of UGT2B protein expression and candidate miRNA levels from human liver samples demonstrated a significant (P<0.05) inverse correlation between UGT2B10 and one of these candidate miRNAs, miR-485-5p. In vitro analysis using luciferase-containing vectors suggested an interaction of miR-485-5p within the 3' untranslated region (UTR) of UGT2B10 (P=0.0073). A significant reduction in luciferase activity (P=0.022) was also observed for luciferase vectors containing the UGT2B7 3' UTR, an effect manifested by one of two potential miR-485-5p-binding sites. UGT2B10 and UGT2B7 activities were probed using nicotine and AZT, respectively, and significant decreases in glucuronidation activity were observed for both substrates in HuH-7 and Hep3B cells (P<0.0003 and P=0.016, and P=0.017 and P=0.030, respectively) upon over-expression of miR-485-5p mimic. This is the first study demonstrating a regulatory role for miR-485-5p for multiple UGT2B enzymes. SIGNIFICANCE STATEMENT: The purpose of this study was to identify novel epigenetic microRNA regulators of the UDP-glucuronosyltransferase (UGT) 2B drug-metabolizing enzymes in healthy human liver samples. Our results indicate that microRNA 485-5p is a novel regulator of UGTs 2B7 and 2B10, which play an important role in the metabolism of many commonly prescribed medications, carcinogens and endogenous compounds. This study identified potential miRNA-UGT2B mRNA interactions using a novel proteomic approach, with in vitro experiments undertaken to validate these interactions.

PMID: 31554697 [PubMed - as supplied by publisher]

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.

Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2018 Dec 01;39(2-3):97-106

Authors: Filipce A, Naumovska Z, Nestorovska AK, Sterjev Z, Brezovska K, Tonic-Ribarska J, Grozdanova A, Suturkova L, Raleva M

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.

PMID: 30864366 [PubMed - indexed for MEDLINE]