FeS2 nanosheets-luminol-O2 chemiluminescence method for determination of venlafaxine hydrochloride, imipramine hydrochloride, and cefazolin sodium.

This study introduces a novel chemiluminescence (CL) approach utilizing FeS2 nanosheets (NSs) catalyzed luminol-O2 CL reaction for the measurement of three pharmaceuticals, namely venlafaxine hydrochloride (VFX), imipramine hydrochloride (IPM), and cefazolin sodium (CEF). The CL method involved the phenomenon of quenching induced by the pharmaceuticals in the CL reaction. To achieve the most quenching efficacy of the pharmaceuticals in the CL reaction, the concentrations of reactants comprising luminol, NaOH, and FeS2 NSs were optimized accordingly. The calibration curves demonstrated exceptional linearity within the concentration range spanning from 4.00 × 10-7 to 1.00 × 10-3 mol L-1, 1.00 × 10-7 to 1.00 × 10-4 mol L-1, and 4.00 × 10-6 to 2.00 × 10-4 mol L-1 with detection limits (3σ) of 3.54 × 10-7, 1.08 × 10-8, and 2.63 × 10-6 mol L-1 for VFX, IPM, and CEF, respectively. This study synthesized FeS2 NSs using a facile hydrothermal approach, and then the synthesized FeS2 NSs were subjected to a comprehensive characterization using a range of spectroscopic methods. The proposed CL method was effective in measuring the aforementioned pharmaceuticals in pharmaceutical formulations as well as different water samples. The mechanism of the CL system has been elucidated.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Enantioselective analysis of venlafaxine and its active metabolites: A review on the separation methodologies.

Venlafaxine (VFX) is a serotonin and norepinephrine reuptake inhibitor chiral drug used in therapy as an antidepressant in the form of a racemate consisting of R- and S-VFX. The two enantiomers of VFX exhibit different pharmacological activities: R-VFX inhibits both norepinephrine and serotonin synaptic reuptake, whereas S-VFX inhibits only the serotonin one. R- and S-VFX are metabolized in the liver to the respective R- and S-O-desmethylvenlafaxine (ODVFX), R- and S-N-desmethylvenlafaxine (NDVFX), and R- and S-N,O-didesmethylvenlafaxine (NODVFX). The pharmacological profile of ODVFX is close to that of VFX, whereas the other two chiral metabolites (NDVFX and NODVFX) have lower affinity for the receptor sites. The pharmacokinetics of the VFX enantiomers appear stereoselective, including the metabolism process. In the past 20 years, several studies describing the enantioselective analysis of R- and S-VFX in pharmaceutical formulations and its chiral metabolites in biological matrices were published. These methods encompass liquid chromatography coupled with UV detection, mass spectrometry, or tandem mass spectrometry, and capillary electrophoresis. This paper reviews the published methods used for the determination of the individual enantiomers of VFX and its chiral metabolites in different matrices.

Rapid, Precise and Affordable Estimation of Venlafaxine and Its Metabolites in Highly Polluted Effluent Waters: Proof-of-Concept for Methodology.

Widespread presence of pharmaceuticals and their metabolites in the environment of industrialized countries is an emerging global concern. Potential contamination of the soil and water by such pharmacologically active substances poses serious ecotoxicological implications. Several studies assessing the long-term ecological risks of pharmaceutical contaminants mainly focus on the risk assessment of the parent drug, while the potential contributions of their metabolites is often neglected. Presence of selective serotonin and norepinephrine reuptake inhibitor venlafaxine, an antidepressant drug, and its metabolites is a matter of serious concern for aquatic systems, since they are difficult to remove by traditional wastewater treatment processes. The concentration of VEN present in water is reportedly one of the highest among pharmaceuticals; however, the long-term effects of its metabolites have not yet been systematically studied. Given the consideration to complex and time-consuming effluent treatment, and realizing the importance of levels of venlafaxine and its metabolites, a simple and accurate analytical method for quick determination is needed. We designed a selective colorimetric method by using oxidative coupling of drug molecules with 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) reagent, to quantify the presence of venlafaxine and its metabolites in aquatic samples, with special emphasis on effluent. The method was validated for selectivity, specificity and robustness as per the ICH Q2 guidelines to assess its suitability in pharmaceutical samples, as well. Highly sensitive and green economical analytical method was successfully established for estimation of venlafaxine and its metabolites in aquatic samples. The method was quick, as it involved minimum processing steps. The method was accurate and linear in the range of 0.5 to 80 ppm and could successfully detect lowest concentration of 1.3 ppm, thus qualifying its applicability for the desired purpose to check the presence of trace levels of VEN or its metabolites in aquatic samples or in pharmaceutical formulations.

Enantiospecific toxicity, distribution and bioaccumulation of chiral antidepressant venlafaxine and its metabolite in loach (Misgurnus anguillicaudatus) co-exposed to microplastic and the drugs.

In present study, we investigated the enantioselective behaviors of the chiral antidepressant venlafaxine and its metabolite O-desmethylvenlafaxine in loach Misgurnus anguillicaudatus (M. anguillicaudatus), as well as effects of microplastic on toxicity, distribution and metabolism through a 40-day co-exposure. The contents of SOD and MDA in loach liver elevated when the loach was exposed to venlafaxine and O-desmethylvenlafaxine. Moreover, co-exposure with microplastic might lead to more adverse effect against loach. The distribution of venlafaxine and O-desmethylvenlafaxine were both detected in loach tissues and liver subcellular. The concentrations of venlafaxine and O-desmethylvenlafaxine were lower in water in microplastic-present treatment. Whilst, more contaminants were accumulated in liver through the "vehicle" (microplastic). Enantioselective behavior of venlafaxine and O-desmethylvenlafaxine occurred with R-enantiomers being preferentially degraded. With microplastic present, the bioaccumulation factor (BAF) of venlafaxine and O-desmethylvenlafaxine in loach tissue amplified more than 10 times. In liver subcellular structure, microplastic may help to transport more compounds into subtle areas and postpone the contaminants metabolism in organisms. The present study for the first time gained an insight into the potential ecological effects and environmental behaviors of combined pollutions of chiral pharmaceuticals and microplastic, which could supply important information for environment risk assessment of concurrent organic pollutants and microplastic.

Venlafaxine Determination in Pharmaceutical Formulation and Serum by Ion-Selective Electrodes.

BACKGROUND: The application of an ion selective technique for the determination of analyte concentrations is considered one of the most economical techniques for quality control purposes. OBJECTIVE: To elaborate and investigate the construction and general performance characteristics of potentiometric PVC membrane sensors for venlafaxine cation (Ven+). METHOD: The sensors are based on the use of the ion association complexes of the venlafaxine cation with phosphotungstate (PT) and silicotungstate (ST) counter anions as ion exchange sites in the plasticized PVC matrix. They are characterized by potentiometric and conductimetric measurements, performed under various conditions. RESULTS: The electrodes showed a fast (response time around 15 s), stable (life span 45 days) and linear (r2 0.995) response for venlafaxine over the concentration range of 5x10-5 - 1x10-2 M venlafaxine hydrochloride. The solubility product of the ion pair and the formation of the precipitation reaction leading to the ion pair, were determined conductimetrically. The electrodes were found to be very selective, precise (RSD < 1%) and applicable to the potentiometric determination of venlafaxine hydrochloride in pure solutions or in pharmaceutical preparation and in biological fluid (serum), without any interference. Validation of the method shows the suitability of the proposed electrodes for use in the quality assessment of venlafaxine hydrochloride. CONCLUSION: Using only a pH meter in combination with the selective electrodes, drug substance or drug product could be determined accurately in a few seconds. In addition, the in-house made electrodes were tested to monitor venlafaxine in serum. Acceptable results were achieved using the standard addition technique.

Application of vermiculite-derived sustainable adsorbents for removal of venlafaxine.

Removal of emerging pollutants, such as pharmaceuticals, from wastewater is a challenge. Adsorption is a simple and efficient process that can be applied. Clays, which are natural and low-cost materials, have been investigated as adsorbent. In this work, raw vermiculite and its three modified forms (expanded, base, and acid/base treated) were tested for removal of a widely used antidepressant, venlafaxine. Adsorption kinetics followed Elovich's model for raw vermiculite while the pseudo-2nd order model was a better fit in the case of other materials. Equilibrium followed Langmuir's model for the raw and the acid/base-treated vermiculite, while Redlich-Peterson's model fitted better the expanded and the base-treated materials. The adsorption capacity of vermiculite was significantly influenced by the changes in the physical and chemical properties of the materials caused by the treatments. The base-treated, raw, and expanded vermiculites showed lower maximum adsorption capacities (i.e., 6.3 ± 0.5, 5.8 ± 0.7, 3.9 ± 0.2 mg g-1, respectively) than the acid/base-treated material (33 ± 4 mg g-1). The acid/base-treated vermiculite exhibited good properties as a potential adsorbent for tertiary treatment of wastewater in treatment plants, in particular for cationic species as venlafaxine due to facilitation of diffusion of the species to the interlayer gallery upon such treatment. Graphical abstract ᅟ.

Validation of an LC-MS/MS method for simultaneous quantification of venlafaxine and its five metabolites in rat plasma and its application in a pharmacokinetic study.

A sensitive, selective, and reliable LC-MS/MS method was developed and validated for simultaneous quantification of venlafaxine (VEN) and its 5 metabolites (ODV, NDV, NNDDV, OHV and NODDV) in rat plasma. The calibration ranges are 15.0 to 6000 ng/mL for VEN, 1.00 to 400 ng/mL for ODV, 5.00 to 2000 ng/mL for NDV, 1.00 to 400 ng/mL for NNDDV, 10.0 to 4000 ng/mL for OHV, and 0.200 to 20.0 ng/mL for NODDV. Briefly, 50 µL of rat plasma was extracted using liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE). The analytes were separated on an Agilent SB-Phenyl (50 mm × 4.6 mm, 3.5 µm) column using a binary gradient of 0.1% formic acid in water versus 0.1% formic acid in acetonitrile at a flow rate of 0.8 mL/min. The method was validated following FDA guidance for bioanalytical method validation. Validated method was successfully applied to a pharmacokinetic study of VEN orally administered to rats.

Mechanical properties and drug release of venlafaxine HCl solid mini matrices prepared by hot-melt extrusion and hot or ambient compression.

Objective/significance: To elucidate the role of plasticizers in different mini matrices and correlate mechanical properties with drug release. METHODS: Cylindrical pellets were prepared by hot-melt extrusion (HME) and mini tablets by hot (HC) and ambient compression (AC). Venlafaxine HCl was the model drug, Eudragit® RSPO the matrix former and citric acid or Lutrol® F127 the plasticizers. The matrices were characterized for morphology, crystallinity, and mechanical properties. The influence of plasticizer's type and content on the extrusion pressure (Pe) during HME and ejection during tableting was examined and the mechanical properties were correlated with drug release parameters. RESULTS: Resistance to extrusion and tablet ejection force were reduced by Lutrol® F127 which also produced softer and weaker pellets with faster release, but harder and stronger HC tablets with slower release. HME pellets showed greater tensile strength (T) and 100 times slower release than tablets. Pe correlated with T and resistance to deformation of the corresponding pellets (r2 = 0.963 and 0.945). For both HME and HC matrices the decrease of drug release with T followed a single straight line (r2 = 0.990) and for HME the diffusion coefficient (De) and retreat rate constant (kb) decreased linearly with T (r2 = 0.934 and 0.972). CONCLUSIONS: Lutrol® F127 and citric acid are efficient plasticizers and Lutrol® F127 is a thermal binder/lubricant in HC compression. The different bonding mechanisms of the matrices were reflected in the mechanical strength and drug release. Relationships established between T and drug release parameters for HME and HC matrices may be useful during formulation work.

GLUT1 -mediated venlafaxine-thiamine disulfide system-glucose conjugates with "lock-in" function for central nervous system delivery.

Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT1 ) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT1 , "lock-in" thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.