RESUMO
Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for Cmax and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC0-∞ , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.
Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Nifedipino/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Cicloexanóis/sangue , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Succinato de Desvenlafaxina/sangue , Interações Medicamentosas , Humanos , Masculino , Fenótipo , Estereoisomerismo , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
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.