RESUMO
AIM: This study aimed to assess the impact of CYP2D6 and CYP2C19 variation on venlafaxine (VEN) at steady state in patients from Trinidad and Tobago of Indian and African descent with major depressive disorder. PATIENTS & METHODS: Patients were phenotyped with dextromethorphan, genotyped for CYP2D6 and CYP2C19, and metabolic ratios for VEN obtained at 2-week intervals. RESULTS: Of 61 patients, 55 were genotyped and phenotyped and 47 completed 8 weeks of VEN treatment. The majority of patients had metabolic ratios for VEN that were consistent with those for dextromethorphan and genotype-predicted phenotype using activity scores. One subject presented with a novel no-function allele, CYP2D6*99. No correlations were observed with CYP2C19 genotype. CONCLUSION: CYP2D6 genotype analysis provides valuable information to individualize drug therapy with VEN.
Assuntos
Citocromo P-450 CYP2D6/genética , Transtorno Depressivo Maior/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Inibidores da Recaptação de Serotonina e Norepinefrina/metabolismo , Cloridrato de Venlafaxina/metabolismo , Adulto , População Negra/genética , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/enzimologia , Feminino , Frequência do Gene , Genótipo , Humanos , Indígenas Sul-Americanos/genética , Masculino , Inibidores da Recaptação de Serotonina e Norepinefrina/sangue , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Trinidad e Tobago , Cloridrato de Venlafaxina/sangue , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
This paper focuses on the development of a novel miniaturized molecularly imprinted solid-phase extraction (MISPE) and ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine venlafaxine (VEN), O-desmethylvenlafaxine (ODV), and N-desmethylvenlafaxine (NDV) in plasma samples. The molecularly imprinted polymer (MIP) was prepared by the precipitation polymerization approach; VEN, metacrylic acid, ethylene glycol dimethacrylate, 2,2-azobisisobutyronitrile, and toluene were used as template, monomer, crosslinker, initiator, and porogen solvent, respectively. MIP and of the non-imprinted control polymer (NIP) sorbents were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. MIP phase presented higher extraction efficiency (MISPE, using plasma samples spiked with VEN) than the NIP phase (84 and 49% recovery rates, respectively). Analysis of other antidepressants with different chemical structures by MISPE-UHPLC-MS/MS attested to the selectivity of the developed MIP. The developed method presented precision assays with coefficients of variation (CV) smaller than 15%; accuracy assays with relative standard error (RSE%) values ranging from -12 to 16%, and linear ranges from 3 to 700ngmL(-1) for VEN, from 5 to 700ngmL(-1) for ODV, and from 3 to 500ngmL(-1) for NDV. The coefficients of determination (r(2)) were higher than 0.995. The lack-of-fit test also attested to the linearity of this method. This method was successfully applied to determine VEN, NDV, and ODV in plasma samples from depressed patients undergoing therapy with VEN.
Assuntos
Cicloexanóis/sangue , Succinato de Desvenlafaxina/sangue , Impressão Molecular , Polímeros/química , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Cloridrato de Venlafaxina/sangue , Acrilatos/química , Antidepressivos/sangue , Antidepressivos/química , Antidepressivos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Cicloexanóis/metabolismo , Depressão/sangue , Depressão/tratamento farmacológico , Succinato de Desvenlafaxina/metabolismo , Humanos , Metacrilatos/química , Microscopia Eletrônica de Varredura , Nitrilas/química , Polimerização , Espectroscopia de Infravermelho com Transformada de Fourier , Tolueno/química , Cloridrato de Venlafaxina/metabolismo , Cloridrato de Venlafaxina/farmacocinética , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
Psoriasis is a chronic inflammatory disease associated with several comorbidities, including depression. Previous studies have shown that inflammatory diseases downregulate the expression and suppress activity of CYP isoforms. Venlafaxine (VLX) is an antidepressant metabolized mainly by CYP2D6 to O-desmethylvenlafaxine (ODV), CYP3A to N-desmethylvenlafaxine (NDV), and CYP2D6 and CYP3A to N,O-didesmethylvenlafaxine (DDV). This study evaluated the influence of psoriasis on the enantioselective pharmacokinetics of VLX. Psoriasis patients (n = 13) and healthy volunteers (n = 11) phenotyped as CYP2D6 extensive (EM) or poor metabolizers (n = 1) received a single oral dose of 150 mg racemic VLX. Plasma concentrations of TNF-α, IFN-γ, IL-6, IL-8, and IL-17 cytokines were higher in EM psoriasis patients when compared with healthy volunteers. IL-6 plasma concentrations varied from 0.4 to 12.9 pg/mL (mean, 2.1 pg/mL) in healthy volunteers and from 0.4 to 29.3 pg/mL (mean, 4.2 pg/mL) in psoriatic patients. VLX pharmacokinetics are enantioselective in healthy volunteers and psoriasis patients phenotyped as EM. Higher AUC values for the (S)-VLX, (S)-NDV, and (S)-DDV enantiomers were observed in healthy volunteers, whereas higher AUC values for (S)-VLX and (R)-ODV were found in psoriasis patients phenotyped as EM. Psoriasis does not alter the pharmacokinetics of the VLX enantiomers probably because of the low levels of IL-6 plasma concentrations.