Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions

LLerena, Adrián; Berecz, Roland; Dorado, Pedro; Garza, César Sanz de la; Norberto, Marı́a Jesús; Cáceres, Macarena C.; Gutiérrez, José Ramón Lomba

doi:10.1016/s1570-0232(02)00661-x

Cited by 46 publications

(39 citation statements)

References 14 publications

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“…The extraction procedures described to isolate RSP and 9-OH RSP from biological matrices are predominantly based on liquid-liquid extraction [3][4][5]8,9,11 . These are very effective and offer high recoveries (> 85 %) with good precision and accuracy, but sample handling requires the use of toxic solvents or multiple extraction steps in order to obtain clean extracts, and this factor is a drawback when the analysis demands to work with a large sample number.…”

Section: E-mail: Cvonples@udeccl; Corresponding Authormentioning

confidence: 99%

Pharmacokinetic Study of Risperidone: Application of a HPLC Method With Solid Phase Extraction

TORRES¹,

C²,

R³

2011

J. Chil. Chem. Soc.

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A new, simplified solid phase extraction procedure for the determination of risperidone and 9-hydroxyrisperidone in human plasma has been developed. This method involves the use of an optimized extraction protocol developed in Waters OASIS ® HLB 30mg 1cc extraction columns using 1 mL of human serum. Separation was performed by HPLC using a Waters XTerra RP-18 (5 µm, 150x4,6 mm) column with a mobile phase consisting in acetonitrile -potassium dihydrogen phosphate 50 mM pH 3.4 (27/73). UV detection at 278 nm was used to quantify analytes, encountering good linearity (r 2 > 0.999) in the 2-100 ng/mL concentration range. The mean recovery was 92.4 % and 92.8 % for risperidone and 9-hydroxyrisperidone respectively, with an intraday -interday precision below 7%, and accuracy below 115 %. The method has been successfully applied in pharmacokinetic studies that require a large sample number.Keywords: Risperidone, 9-hydroxyrisperidone, solid phase extraction. 1.-INTRODUCTIONRisperidone (RSP, figure 1) is a benzoisoxazole derivative that is clinically used as an atypical antipsychotic. Since its introduction in the 1990s, it has been considered to be a first-rate choice in the treatment of schizophrenia and other mental disorders because of its pharmacodynamics 1 (selective blocking of 5-HT2 and D2 receptors in brain), providing effective management of positive, negative and cognitive symptoms of schizophrenia with a low profile of extrapyramidal and autonomic side effects 2 .Several methods have been proposed for therapeutic and toxicological monitoring of RSP and 9-hydroxyrisperidone (9-OH RSP, figure 1). These are more-or-less sensitive depending on the detection mode used. UV detection offers simplicity but higher limit of quantitation (LOQ=2 ng/ml) and presence of interferents if the extraction procedure is not selective 3.4.5 . Electrochemical detection offers lower LOQ (< 0.5 ng/mL) but lacks selectivity and sample and standard preparation require high purity reagents 6,7 . Ultimately, mass spectrometry detection offers high sensitivity and selectivity, but the cost is not accessible for most laboratories, especially in Latin America 8-11 . e-mail: cvonples@udec.cl; corresponding authorFigure 1: Chemical structures of Risperidone, 9-OH hydroxyrisperidone and Clozapine.The extraction procedures described to isolate RSP and 9-OH RSP from biological matrices are predominantly based on liquid-liquid extraction [3][4][5]8,9,11 . These are very effective and offer high recoveries (> 85 %) with good precision and accuracy, but sample handling requires the use of toxic solvents or multiple extraction steps in order to obtain clean extracts, and this factor is a drawback when the analysis demands to work with a large sample number. On the other hand, solid phase extraction (SPE) procedures offer an easier sample handling but the results are reliable only if the analyst avoids sorbent drying 7,10,[12][13][14][15] . In our laboratory, we tested the properties of the sorbent included in Waters OASIS ® HLB cartridges be...

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Section: E-mail: Cvonples@udeccl; Corresponding Authormentioning

confidence: 99%

Pharmacokinetic Study of Risperidone: Application of a HPLC Method With Solid Phase Extraction

TORRES¹,

C²,

R³

2011

J. Chil. Chem. Soc.

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“…The plasma levels of risperidone and 9-hydroxyrisperidone were ascertained through a wellestablished high-performance liquid chromatography procedure. 34 Genomic DNA was extracted from peripheral blood using a standard phenol/ chloroform method. Determination of genotypes was carried out after clinical outcomes assessment and was completed by researchers who were blind to the outcomes of assessment.…”

Section: Clinical Samplementioning

confidence: 99%

Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study

Xing

et al. 2010

Eur J Hum Genet

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Risperidone is a widely used atypical antipsychotic agent that produces considerable interindividual differences in patient response. We investigated the pharmacogenetic relationship between the brain-derived neurotrophic factor (BDNF) gene and response to risperidone in 127 Han Chinese schizophrenic patients. Three functional polymorphisms, (GT) n dinucleotide repeat polymorphism, C-270T, and the rs6265G/A single-nucleotide polymorphism (SNP), were genotyped and analyzed for association, with reduction of Brief Psychiatric Rating Scale (BPRS) scores following an 8-week period of risperidone monotherapy. For individual polymorphic analysis, we found that the frequency of the 230-bp allele of the (GT) n polymorphism was much higher in responders (47.95%) than in nonresponders (32.41%) and the difference was statistically significant even after Bonferroni's adjustment (for the 230-bp allele: adjusted P¼0.039). For haplotype-based analyses of the three polymorphisms, no positive finding was observed in the global test, but in specific haplotype tests, two haplotypes were also significantly related to response to risperidone (for haplotype 230-bp/C-270/rs6265G: P¼0.0009; for haplotype 234-bp/C-270/rs6265A: P¼0.043), indicating that patients with the 230-bp allele of the (GT) n polymorphism or the 230-bp/C-270/rs6265G haplotype responded better to risperidone than those with other alleles or haplotypes, and that the positive effect of the individual haplotype 230-bp/C-270/rs6265G was mainly driven by the 230-bp allele. These findings demonstrate that the individual and combinatorial genetic variants in the BDNF gene might have a role in the therapeutic response to risperidone in the Han Chinese population.

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“…A RSP é biotransformada principalmente no fígado, através das isoenzimas do citocromo P450, principalmente por 9-hidroxilação e secundariamente por N-dealquilação e 7-hidroxilação (Avenoso et al, 2000;Spina et al, 2001). O principal metabólito circulante da RSP é a 9OH-RSP (Figura 4B), formada predominantemente através da reação de catalisação pela enzima CYP2D6 (Aravagiri e Marder, 2000;Avenoso et al, 2000;Llerena et al, 2003). A principal rota de eliminação da RSP é a renal (Cánovas et al, 2009).…”

Section: Farmacocinéticaunclassified

“…A 9OH-RSP tem propriedades farmacológicas semelhantes às da RSP (70% do efeito farmacológico da RSP), sendo considerada a fração ativa o somatório das concentrações séricas da RSP e da 9OH-RSP (Heykants et al, 1994;Llerena et al, 2003). Alguns fatores podem influenciar nos níveis séricos da fração ativa, tais como: idade, lesões hepáticas e renais, genótipo da CYP2D6 e administração concomitante de outros medicamentos (Avenoso et al, 2000).…”

Section: Farmacocinéticaunclassified

“…As técnicas analíticas utilizadas para o controle de qualidade, determinação e quantificação da RSP são: espectrofotometria no ultravioleta, eletroforese capilar, cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC-MS), sendo a última a mais empregada nestes tipos de análises (Woestenborghs et al,1992 ;Olesen e Linnet, 1997 ;Balant-Gorgia et al, 1999 ;Nagasaki et al, 1999 ;Avenoso et al, 2000;Titier et al 2002 ;Llerena et al, 2003;Titier et al, 2003;Eerdekens et al, 2004Riedel et al, 2005Bharathi et al, 2007 ;Zhang et al, 2007b).…”

Section: Aspectos Analíticosunclassified

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Comparação da bioequivalência de duas formulações da risperidona

Belotto¹

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LISTA DE ABREVIATURAS 1,5; 3; 5; 8; 12; 24; 48; 72; 96 e 120 horas após a administração da medicação. A determinação da bioequivalência entre os dois medicamentos deu-se através da comparação dos parâmetros farmacocinéticos: concentração plasmática máxima (C max ), tempo para atingir a concentração plasmática máxima (T max ) e área sobre a curva de decaimento plasmático (ASC T ). Os resultados obtidos foram submetidos à análise de variância (ANOVA) e foi adotado o intervalo de confiança de 90% (IC 90%). Os valores médios para C max , T max e ASC T para RSP para os medicamentos referência e teste foram 16,02 ng/mL; 1,5 h e 348,94 ng.h/mL e 12,65 ng/mL; 1,5 h e 286,03 ng.h/mL, respectivamente. Já os valores médios para C max , T max e ASC T para 9OH-RSP para os medicamentos referência e teste foram 21,00 ng/mL; 5,0 h e 821,40 ng.h/mL e 17,85 ng/mL; 5,0 h e 632,92 ng.h/mL. Os valores de IC 90% para C max e ASC T para RSP para os medicamentos referência e teste foram 74 a 82% e 76 a 85%, respectivamente, e os valores de IC 90% para os mesmos parâmetros para 9OH-RSP foram 83 a 87% e 75 a 78%, respectivamente. Os resultados demonstraram diferenças significativas entre os medicamentos testados, o que permite concluir que os mesmos não são bioequivalentes e, portanto, não podem ser intercambiáveis.Descritores: equivalência terapêutica, risperidona, cromatografia líquida de alta pressão, farmacocinética. Brazil has launched programmes of public policies aiming to improve essential medicines access for the population since 1964. It was created in 1999 the National Agency for Sanitary Vigilance, which introduced the generic medicines in the Brazilian market, which already had the reference and the pharmaceutical equivalent ones. The objective of this study was to evaluate the bioequivalence and interchangeability between two antipsychotics (reference and pharmaceutical equivalent) used by the Institute of Psychiatry, Hospital of the Universidade de São Paulo, containing 2 mg of risperidone. It was developed and validated a high-performance liquid chromatography coupled to mass spectrometry method for the determination in plasma of risperidone (RSP) and its main metabolite, 9-hydroxy-risperidone (9OH-RSP). To assess bioequivalence between the medicines it was recruited 22 healthy volunteers, which took part in a clinical cross and random studies. The blood collections were performed on heparinizades tubes (5 ml) and runtimes collections were 0 (before medication); 0.25; 0.5; 1; 1.5; 3; 5; 8; 12; 24; 48; 72; 96 and 120 hours after the administration of medication. The determination of bioequivalence between the two drugs was achieved by a comparison of the following pharmacokinetic parameters: plasma concentration (C max ), time to achieve C max (T max ), and area under the plasma concentration-time curve (AUC T ).Results were subjected to analysis of variance (ANOVA), adopting a confidence interval CI 90%. The average values for Cmax, Tmax and AUCT for RSP were 16.02 ng/ml, 1.5 h and 348.94 ng.h/ml for reference medicines a...

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Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions

Cited by 46 publications

References 14 publications

Pharmacokinetic Study of Risperidone: Application of a HPLC Method With Solid Phase Extraction

Pharmacokinetic Study of Risperidone: Application of a HPLC Method With Solid Phase Extraction

Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study

Comparação da bioequivalência de duas formulações da risperidona

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