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1.
Cell Biochem Funct ; 41(1): 98-111, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36478589

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration-approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID-19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID-19 is still unknown. Fluvoxamine was docked with 11 SARS-CoV-2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain-like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7-MTase ((N7-guanine)-methyltransferase)-fluvoxamine, Mpro-fluvoxamine, and PLpro-fluvoxamine complexes are stable, with the lowest binding free energies of -105.1, -82.7, and - 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS-CoV-2.


Subject(s)
COVID-19 Drug Treatment , Fluvoxamine , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/therapy , Fluvoxamine/chemistry , Fluvoxamine/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Coronavirus 3C Proteases
2.
Photochem Photobiol Sci ; 14(5): 982-94, 2015 May.
Article in English | MEDLINE | ID: mdl-25793560

ABSTRACT

Despite the numerous concerns that have been raised in relation to considering 0(th), 1(st) and 2(nd)-order kinetic treatments for photodegradation characterisation and assessment of drugs, they still are employed, as they are the only tools available for these types of studies. The recently developed Φ-order kinetic models have opened new perspectives in the treatment of photoreaction kinetics and stand as the best known alternative to the classical approach. The Φ-order kinetics have been applied here to Fluvoxamine (Fluvo) with the aim of setting out a detailed and comprehensive procedure capable of rationalising photodegradation/photostability of drugs and proposing a platform for photosafety studies. Our results prove that quantum yields of drugs (0.0016 < Φ(λirr)(Fluvo) < 0.43) should a priori be considered wavelength-dependent; their photostabilisation (up to 75% for Fluvo) by means of absorption competitors can explicitly be related to a decrease of the photokinetic factor, and photoreversible drugs can be developed into efficient actinometers (as Fluvoxamine in the 260-290 nm range). A pseudo-rate-constant factor was proposed as a descriptive parameter, circumventing the limitations of overall rate-constants and allowing a comparison between kinetic data of drugs obtained under different conditions.


Subject(s)
Fluvoxamine/chemistry , Fluvoxamine/radiation effects , Photochemical Processes , Chromatography, High Pressure Liquid , Isomerism , Kinetics , Light , Linear Models , Models, Chemical , Molecular Structure , Solutions , Tartrazine/chemistry , Tartrazine/radiation effects , Water/chemistry
3.
Photochem Photobiol Sci ; 12(5): 751-9, 2013 May.
Article in English | MEDLINE | ID: mdl-23321854

ABSTRACT

Persistent fluorinated substances, such as the fluorine-bearing pharmaceutical drugs Fluoxetine (FLX; Prozac) and Fluvoxamine maleate (FOM) together with several other substrates (fluorobenzoic acid and fluoroaliphatic model compounds), were photochemically defluorinated and degraded under UVC illumination in relatively good yields in the presence of a wide band gap metal oxide (ß-Ga2O3) in heterogeneous aqueous media. The formation of fluoride ions increased with increasing illumination time under an inert nitrogen atmosphere, the transformation of the aromatic moiety was slower under these conditions, but nonetheless it did occur. The optimal amount of ß-Ga2O3 loading for defluorination was 50 mg in aqueous media (0.10 mM, 100 mL); the optimal pH to defluorinate FLX was pH 6. Platinization (1 wt%) of the gallium oxide particles enhanced defluorination under an inert nitrogen atmosphere, but was decreased under an oxygen atmosphere; however, in the latter case the degradation of the substrates was facilitated as witnessed by loss of the aromatic moiety. The Ames test on the intermediate products from the photodegradation of FLX and 4-(trifluoromethyl)benzoic acid after long illumination times revealed that none were mutagenic.


Subject(s)
Fluoxetine/chemistry , Fluvoxamine/chemistry , Gallium/chemistry , Fluorides/chemistry , Halogenation , Hydrogen-Ion Concentration , Kinetics , Oxidation-Reduction , Photolysis , Toluene/analogs & derivatives , Toluene/chemistry , Ultraviolet Rays , Water/chemistry
4.
Tijdschr Psychiatr ; 55(2): 113-21, 2013.
Article in Dutch | MEDLINE | ID: mdl-23408363

ABSTRACT

BACKGROUND: The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence. AIM: Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine. METHOD: A review of the literature with Ovid Medline and the presentation of a case series (N=7). RESULTS: Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine. CONCLUSION: Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.


Subject(s)
Antipsychotic Agents/blood , Clozapine/blood , Drug Interactions , Drug Synergism , Fluvoxamine/blood , Antipsychotic Agents/chemistry , Antipsychotic Agents/therapeutic use , Clozapine/chemistry , Clozapine/therapeutic use , Fluvoxamine/chemistry , Fluvoxamine/therapeutic use , Humans , Schizophrenia/drug therapy
5.
Mol Pharmacol ; 82(5): 824-34, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22859721

ABSTRACT

Cytochrome P450 46A1 (cholesterol 24-hydroxylase) is an important brain enzyme that may be inhibited by structurally distinct pharmaceutical agents both in vitro and in vivo. To identify additional inhibitors of CYP46A1 among U.S. Food and Drug Administration-approved therapeutic agents, we used in silico and intuitive predictions and evaluated some of the predicted binders in the enzyme and spectral binding assays. We tested a total of 298 marketed drugs for the inhibition of CYP46A1-mediated cholesterol hydroxylation in vitro and found that 13 of them reduce CYP46A1 activity by >50%. Of these 13 inhibitors, 7 elicited a spectral response in CYP46A1 with apparent spectral K(d) values in a low micromolar range. One of the identified tight binders, the widely used antidepressant fluvoxamine, was cocrystallized with CYP46A1. The structure of this complex was determined at a 2.5 Å resolution and revealed the details of drug binding to the CYP46A1 active site. The NH(2)-containing arm of the Y-shaped fluvoxamine coordinates the CYP46A1 heme iron, whereas the methoxy-containing arm points away from the heme group and has multiple hydrophobic interactions with aliphatic amino acid residues. The CF(3)-phenyl ring faces the entrance to the substrate access channel and has contacts with the aromatic side chains. The crystal structure suggests that only certain drug conformers can enter the P450 substrate access channel and reach the active site. Once inside the active site, the conformer probably further adjusts its configuration and elicits the movement of the protein side chains.


Subject(s)
Antidepressive Agents/chemistry , Fluvoxamine/chemistry , Protease Inhibitors/chemistry , Steroid Hydroxylases/antagonists & inhibitors , Animals , Brain/drug effects , Brain/metabolism , Cattle , Cholesterol/metabolism , Cholesterol 24-Hydroxylase , Computer Simulation , Crystallization , Crystallography, X-Ray , Entropy , Enzyme Assays , Humans , Hydroxylation , In Vitro Techniques , Microsomes/drug effects , Microsomes/metabolism , Models, Molecular , Molecular Structure , Protease Inhibitors/pharmacology , Protein Binding , Quantitative Structure-Activity Relationship , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Stereoisomerism , Steroid Hydroxylases/chemistry , Tranylcypromine/chemistry , Water
6.
Eur J Med Chem ; 220: 113533, 2021 Aug 05.
Article in English | MEDLINE | ID: mdl-34049262

ABSTRACT

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.


Subject(s)
Fluoxetine/pharmacology , Fluvoxamine/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Dose-Response Relationship, Drug , Fluoxetine/chemical synthesis , Fluoxetine/chemistry , Fluvoxamine/chemical synthesis , Fluvoxamine/chemistry , Humans , Ligands , Models, Molecular , Molecular Structure , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity Relationship
7.
J Fluoresc ; 19(3): 463-71, 2009 May.
Article in English | MEDLINE | ID: mdl-18949539

ABSTRACT

A highly sensitive and simple spectrofluorimetric method has been developed and validated for the determination of the antidepressant fluvoxamine (FXM) in its dosage forms and plasma. The method was based on nucleophilic substitution reaction of FXM with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in an alkaline medium (pH 8) to form a highly fluorescent derivative that was measured at 535 nm after excitation at 470 nm. The factors affecting the reaction was carefully studied and optimized. The kinetics of the reaction was investigated, and the reaction mechanism was presented. Under the optimized conditions, linear relationship with good correlation coefficient (0.9995) was found between the fluorescence intensity and FXM concentration in the range of 65-800 ng ml(-1). The limits of detection and quantitation for the method were 21 and 64 ng ml(-1), respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2.17%. The proposed method was successfully applied to the determination of FXM in its pharmaceutical tablets with good accuracy; the recovery values were 97.8-101.4 +/- 1.08-2.75%. The results obtained by the proposed method were comparable with those obtained by the official method. The high sensitivity of the method allowed its successful application to the analysis of FXM in spiked human plasma. The proposed method is superior to the previously reported spectrofluorimetric method for determination of FXM in terms of its simplicity. The proposed method is practical and valuable for its routine application in quality control and clinical laboratories for analysis of FXM.


Subject(s)
4-Chloro-7-nitrobenzofurazan/chemistry , Antidepressive Agents/analysis , Antidepressive Agents/chemistry , Fluvoxamine/analysis , Fluvoxamine/chemistry , Antidepressive Agents/administration & dosage , Antidepressive Agents/blood , Calibration , Fluvoxamine/administration & dosage , Fluvoxamine/blood , Humans , Hydrochloric Acid/chemistry , Hydrogen-Ion Concentration , Kinetics , Reproducibility of Results , Sensitivity and Specificity , Solvents/chemistry , Spectrometry, Fluorescence , Temperature , Time Factors
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 72(4): 897-902, 2009 May.
Article in English | MEDLINE | ID: mdl-19135409

ABSTRACT

Spectrophotometric study was carried out, for the first time, to investigate the reaction between the antidepressant fluvoxamine (FXM) and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 9), an orange-colored product exhibiting maximum absorption peak (lambda(max)) at 470nm was produced. The kinetics of the reaction was investigated and its activation energy was found to be 2.65kcalmol(-1). Because of this low activation energy, the reaction proceeded easily. The stoichiometry of the reaction was determined and the reaction mechanism was postulated. This color-developing reaction was successfully employed in the development of simple and rapid spectrophotometric method for determination of FXM in its pharmaceutical dosage forms. Under the optimized reaction conditions, Beer's law correlating the absorbance (A) with FXM concentration (C) was obeyed in the range of 0.6-8microgml(-1). The regression equation for the calibration data was A=0.0086+0.1348C, with good correlation coefficient (0.9996). The molar absorptivity (epsilon) was 5.9x10(4)lmol(-1)cm(-1). The limits of detection and quantification were 0.2 and 0.6microgml(-1), respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2%. The proposed method was successfully applied to the determination of FXM in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.47+/-0.96%. The results obtained by the proposed method were comparable with those obtained by the official method. The proposed method is superior to all the previously reported spectrophotometric methods for determination of FXM in terms of its simplicity and sensitivity. The method is practical and valuable for its routine application in quality control laboratories for analysis of FXM.


Subject(s)
Antidepressive Agents, Second-Generation/chemistry , Fluvoxamine , Naphthoquinones/chemistry , Spectrophotometry/methods , Dosage Forms , Fluvoxamine/administration & dosage , Fluvoxamine/chemistry , Molecular Structure , Reproducibility of Results
9.
CPT Pharmacometrics Syst Pharmacol ; 8(5): 296-307, 2019 05.
Article in English | MEDLINE | ID: mdl-30762305

ABSTRACT

This study provides whole-body physiologically-based pharmacokinetic models of the strong index cytochrome P450 (CYP)1A2 inhibitor and moderate CYP3A4 inhibitor fluvoxamine and of the sensitive CYP1A2 substrate theophylline. Both models were built and thoroughly evaluated for their application in drug-drug interaction (DDI) prediction in a network of perpetrator and victim drugs, combining them with previously developed models of caffeine (sensitive index CYP1A2 substrate), rifampicin (moderate CYP1A2 inducer), and midazolam (sensitive index CYP3A4 substrate). Simulation of all reported clinical DDI studies for combinations of these five drugs shows that the presented models reliably predict the observed drug concentrations, resulting in seven of eight of the predicted DDI area under the plasma curve (AUC) ratios (AUC during DDI/AUC control) and seven of seven of the predicted DDI peak plasma concentration (Cmax ) ratios (Cmax during DDI/Cmax control) within twofold of the observed values. Therefore, the models are considered qualified for DDI prediction. All models are comprehensively documented and publicly available, as tools to support the drug development and clinical research community.


Subject(s)
Caffeine/pharmacokinetics , Cytochrome P-450 CYP1A2/metabolism , Fluvoxamine/pharmacokinetics , Midazolam/pharmacokinetics , Rifampin/pharmacokinetics , Theophylline/pharmacokinetics , Administration, Oral , Algorithms , Area Under Curve , Caffeine/administration & dosage , Caffeine/chemistry , Cytochrome P-450 CYP1A2/chemistry , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Fluvoxamine/administration & dosage , Fluvoxamine/chemistry , Humans , Midazolam/administration & dosage , Midazolam/chemistry , Models, Biological , Models, Molecular , Rifampin/administration & dosage , Rifampin/chemistry , Theophylline/administration & dosage , Theophylline/chemistry
10.
J Pharm Biomed Anal ; 46(4): 707-22, 2008 Mar 13.
Article in English | MEDLINE | ID: mdl-18206329

ABSTRACT

A simple and selective (19)F NMR method has been validated for the quantitation of fluoxetine (FLX) and fluvoxamine (FLV) in methanol solutions and in human plasma and urine. The regression equations for FLX and FLV showed a good linearity in the range of 1.4-620 microg mL(-1) (3.3 x 10(-6)-1.8 x 10(-3) mol L(-1)) with a limit of detection of approximately 0.5 microg mL(-1) (1.3 x 10(-6) mol L(-1)) and a limit of quantification of approximately 2 microg mL(-1) (4.6 x 10(-6) mol L(-1)). The precision of the assay depends on the concentrations and is comprised between 1.5 and 9.5% for a range of concentrations between 1.2 x 10(-3) and 3.2 x 10(-6) mol L(-1). The accuracy evaluated through recovery studies ranged from approximately 96 to 103% in methanol solutions and in urine, and from approximately 93 to 104% in plasma, with standard deviations <7.5%. The low sensitivity of the method precludes its use for the assay of these antidepressants in biofluids at least at therapeutic doses as the ranges of FLX and FLV plasma levels are 0.15-0.5 microg mL(-1) and 0.15-0.25 microg mL(-1), respectively. The method was applied successfully to the determination of FLX and FLV contents in pharmaceutical samples (brand-named and generic) purchased in several countries or via the Internet. All the commercial formulations contain the active ingredient in the range 94-103% of stated concentration. A "signature" of the formulations (solid and liquid) was obtained with 2D Diffusion-Ordered SpectroscopY (DOSY) (1)H NMR which allowed the characterisation of the active ingredient and excipients present in the formulations studied. Finally, the DOSY separation of FLX and FLV whose molecular weights are very close was obtained by using beta-cyclodextrin as host-guest complexing agent.


Subject(s)
Fluoxetine/analysis , Fluvoxamine/analysis , Magnetic Resonance Spectroscopy/methods , Chemistry, Pharmaceutical , Fluoxetine/chemistry , Fluoxetine/urine , Fluvoxamine/chemistry , Fluvoxamine/urine , Humans , Internet , beta-Cyclodextrins/chemistry
11.
J Pharm Biomed Anal ; 48(1): 49-56, 2008 Sep 10.
Article in English | MEDLINE | ID: mdl-18565712

ABSTRACT

The technique equilibrium sampling through membrane (ESTM) was extended to measuring the free drug concentration in solutions of drug and protein. Bjerrum and Scatchard plots were employed for characterizing individual drug binding to pure human blood proteins. Four drugs were investigated as a model system: fluvoxamine and ropivacaine which dominantly bind to alpha-acid glycoprotein (AGP), and R,S-ibuprofen and S-ketoprofen which highly bind to human serum albumin (HSA). The level of drug binding to AGP and HSA relied on drug and protein concentrations. Bjerrum and Scatchard plots revealed high affinity constants (Ka) at low protein concentration. Both Bjerrum and Scatchard plots of fluvoxamine and ropivacaine binding to AGP showed one specific binding site (n1=1) with ropivacaine Ka value close to 5 times higher than the Ka of fluvoxamine at 22.9 microM AGP concentration. Bjerrum plots of ketoprofen and ibuprofen gave total number of binding sites or bound molecules of 6-7, which did not depend on the drug or protein concentration. Scatchard plots of ketoprofen and ibuprofen exhibited two binding sites (n1 and n2) at 0.15 microM and 0.75 microM HSA concentrations. On one hand, at 0.15 microM HSA, ketoprofen and ibuprofen were bound to site I at n1=1.2 and n1=1.0, respectively. However, at 0.75 microM HSA, ketoprofen and ibuprofen were bound to site I at n1=1.2 and n1=1.9, respectively. On the other hand, site II, at 0.15 microM HSA, interacted with ketoprofen and ibuprofen at n2=5.6 and 6.7, respectively. However, at 0.75 microM HSA, site II interacted with ketoprofen at n2=7.4 and ibuprofen at n2=6.2. It would be concluded that, upon mixing ketoprofen and ibuprofen in a HSA solution, a ketoprofen-ibuprofen interaction would most likely occur at site II in HSA.


Subject(s)
Pharmaceutical Preparations/metabolism , Proteins/metabolism , Amides/chemistry , Amides/metabolism , Anesthetics, Local/chemistry , Anesthetics, Local/metabolism , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antigens/chemistry , Antigens/metabolism , Binding Sites , Binding, Competitive , Blood Proteins/chemistry , Blood Proteins/metabolism , Fluvoxamine/chemistry , Fluvoxamine/metabolism , Glycoproteins/chemistry , Glycoproteins/metabolism , Humans , Ibuprofen/chemistry , Ibuprofen/metabolism , Ketoprofen/chemistry , Ketoprofen/metabolism , Kinetics , Membranes, Artificial , Pharmaceutical Preparations/chemistry , Protein Binding/drug effects , Proteins/chemistry , Ropivacaine , Serum Albumin/chemistry , Serum Albumin/metabolism , Stereoisomerism
12.
Nat Struct Mol Biol ; 25(2): 170-175, 2018 02.
Article in English | MEDLINE | ID: mdl-29379174

ABSTRACT

Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity.


Subject(s)
Antidepressive Agents/chemistry , Fluvoxamine/chemistry , Paroxetine/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin Plasma Membrane Transport Proteins/chemistry , Sertraline/chemistry , Binding Sites , Chemistry, Pharmaceutical , Crystallography, X-Ray , Humans , Kinetics , Mutation , Protein Binding
13.
Environ Sci Pollut Res Int ; 25(7): 6890-6898, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29270897

ABSTRACT

Pharmaceuticals in the aquatic environment may be decomposed by abiotic and biotic factors. Photodegradation is the most investigated abiotic process, as it occurs in the natural environment and may be applied in wastewater treatment technology. Although pharmaceuticals are detected in effluents and surface water in a mixture, the photodegradation process is mainly evaluated with single compounds. The photodegradation of fluoxetine (FLU) and fluvoxamine (FLX) in the presence of diclofenac (DCF) and triclosan (TCS) was investigated with HPLC and bioassay. FLU did not degrade under UV-Vis irradiation in SunTest CPS+ either with or without the tested additives, although small amounts of desmethyl fluoxetine and 4-(trifluoromethyl)phenol were formed. In contrast, during irradiation, FLX isomerized to cis-FLX. This process was enhanced by DCF and TCS, but to a lesser degree than by humic acids. Thus, the presence and composition of the matrix should be considered in the environmental risk assessment of pharmaceuticals. As the toxicity of the tested solutions depended only on the concentration of the tested drugs, it was suggested that the biological activity of the photodegradation products was lower than that of the parent compounds.


Subject(s)
Fluoxetine/chemistry , Fluvoxamine/chemistry , Photolysis , Waste Disposal, Fluid/methods , Wastewater/toxicity , Water Pollutants, Chemical/chemistry , Ciliophora/drug effects , Humic Substances/analysis
14.
J Pharm Biomed Anal ; 43(4): 1444-51, 2007 Mar 12.
Article in English | MEDLINE | ID: mdl-17157470

ABSTRACT

A simple, specific and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the assay of fluvoxamine in human plasma and urine. The method was based on reaction of fluvoxamine with 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS) forming orange colored product. The fluvoxamine-NQ derivative was separated by isocratic reversed-phase HPLC and detected at 450 nm. The chromatographic conditions were as follows: Phenomenex C(18) (250 mm x 4.6 mm i.d., 5 microm) column, mobile phase consisting of acetonitrile/water (80:20 v/v) at a flow rate of 1 ml/min. Tryptamine was selected as an internal standard. The assay was linear over the concentration range of 5-145 and 2-100 ng/ml for plasma and urine, respectively. The limits of detection (LOD) were 1.4 and 1 ng/ml for plasma and urine estimation at a signal-to-noise (S/N) ratio of 3. The limits of quantification (LOQ) were 5 and 2 ng/ml for plasma and urine, respectively. The extraction recoveries were found to be 96.66+/-0.69 and 96.73+/-2.17% for plasma and urine, respectively. The intra-day and inter-day standard deviations (S.D.) were less than 1. The method indicated good performance in terms of specificity, linearity, detection and quantification limits, precision and accuracy. This assay was demonstrated to be applicable for clinical pharmacokinetic studies.


Subject(s)
Chromatography, High Pressure Liquid/methods , Fluvoxamine/blood , Fluvoxamine/urine , Coloring Agents , Fluvoxamine/chemistry , Fluvoxamine/pharmacokinetics , Humans , Molecular Structure , Naphthoquinones/chemistry , Sensitivity and Specificity , Spectrophotometry , Tryptamines/chemistry
15.
J Pharm Biomed Anal ; 129: 229-236, 2016 Sep 10.
Article in English | MEDLINE | ID: mdl-27433988

ABSTRACT

Generic Parallel Artificial Liquid Membrane Extraction (PALME) methods for non-polar basic and non-polar acidic drugs from human plasma were investigated with respect to phospholipid removal. In both cases, extractions in 96-well format were performed from plasma (125µL), through 4µL organic solvent used as supported liquid membranes (SLMs), and into 50µL aqueous acceptor solutions. The acceptor solutions were subsequently analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using in-source fragmentation and monitoring the m/z 184→184 transition for investigation of phosphatidylcholines (PC), sphingomyelins (SM), and lysophosphatidylcholines (Lyso-PC). In both generic methods, no phospholipids were detected in the acceptor solutions. Thus, PALME appeared to be highly efficient for phospholipid removal. To further support this, qualitative (post-column infusion) and quantitative matrix effects were investigated with fluoxetine, fluvoxamine, and quetiapine as model analytes. No signs of matrix effects were observed. Finally, PALME was evaluated for the aforementioned drug substances, and data were in accordance with European Medicines Agency (EMA) guidelines.


Subject(s)
Pharmaceutical Preparations/chemistry , Phospholipids/chemistry , Plasma/chemistry , Technology, Pharmaceutical/methods , Chromatography, Liquid/methods , Fluoxetine/chemistry , Fluvoxamine/chemistry , Humans , Lysophosphatidylcholines/chemistry , Membranes, Artificial , Phosphatidylcholines/chemistry , Quetiapine Fumarate/chemistry , Sphingomyelins/chemistry , Tandem Mass Spectrometry/methods
16.
Clin Pharmacokinet ; 27(3): 175-90, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7988100

ABSTRACT

Fluvoxamine is a selective inhibitor of serotonin reuptake that is widely used in the management of depression. Following oral administration, the drug is absorbed efficiently from the gastrointestinal tract. Peak plasma concentrations are usually observed within 2 to 8 hours postdose for capsules and film-coated tablets and within 4 to 12 hours for enteric-coated tablets. Despite complete absorption, oral bioavailability may be incomplete probably because of first-pass metabolism. Approximately 77% of fluvoxamine is plasma protein bound. Only negligible amounts of fluvoxamine are excreted unchanged in urine. The drug is extensively biotransformed, mostly by oxidation, and at least 11 different metabolites have been detected in human urine. None of the metabolites is known to possess significant pharmacological activity. Following administration of single doses, fluvoxamine shows a biphasic elimination with a mean terminal elimination half-life of about 15 to 20 hours. Steady-state plasma fluvoxamine concentrations are achieved 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single-dose data. Preliminary data also suggest that plasma drug concentrations may increase nonlinearly with increasing daily dosage. The relationship between plasma fluvoxamine concentration and clinical response has not been clearly defined. Fluvoxamine pharmacokinetics are substantially unaltered in the elderly, whereas higher plasma drug concentrations (relative to dose) are observed in patients with alcoholic cirrhosis of the liver. Fluvoxamine inhibits oxidative drug metabolising enzymes and, therefore, causes a number of clinically significant drug interactions. Drugs whose metabolic elimination is impaired by fluvoxamine include tricyclic antidepressants, alprazolam, bromazepam, diazepam, theophylline, phenazone (antipyrine), propranolol, warfarin, methadone and carbamazepine.


Subject(s)
Fluvoxamine/pharmacokinetics , Animals , Dose-Response Relationship, Drug , Drug Interactions , Fluvoxamine/chemistry , Humans
17.
Br J Pharmacol ; 139(5): 887-98, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12839862

ABSTRACT

1. Pharmacological blockade of the Human ether-a-go-go related gene (HERG) potassium channel is commonly linked with acquired long QT syndrome and associated proarrhythmia. The objectives of this study were (i) to identify and characterise any inhibitory action on HERG of the selective-serotonin re-uptake inhibitor fluvoxamine, (ii) to then determine whether fluvoxamine shared the consensus molecular determinants of HERG blockade of those drugs so far tested. 2. Heterologous HERG potassium current (I(HERG)) was measured at 37 degrees C, using the whole-cell patch-clamp technique, from a mammalian cell line (Human embryonic kidney 293) expressing HERG channels. I(HERG) tails, following repolarisation from +20 to -40 mV, were blocked by fluvoxamine with an IC(50) of 3.8 micro M. 3. Blockade of wild-type HERG was of extremely rapid onset (within 10 ms) and showed voltage dependence, with fluvoxamine also inducing a leftward shift in voltage-dependent activation of I(HERG). Characteristics of block were consistent with a component of closed channel (or extremely rapidly developing open channel) blockade and dependence on open and inactivated channel states. The attenuated-inactivation mutation S631A partially reduced the blocking effect of fluvoxamine. 4. The S6 mutations, Y652A and F656A, and the pore helix mutant S631A only partially attenuated blockade by fluvoxamine at concentrations causing profound blockade of wild-type HERG. 5. All HERG-blocking pharmaceuticals studied to date have been shown to block F656 mutant channels with over 100-fold reduced potency compared to their blockade of the wild-type channel. Fluvoxamine is therefore quite distinct in this regard from previously studied agents.


Subject(s)
Amino Acid Substitution/genetics , Cation Transport Proteins , DNA-Binding Proteins , Fluvoxamine/pharmacology , Mutation , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated , Potassium Channels/genetics , Trans-Activators , Cell Line , Dose-Response Relationship, Drug , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels , Fluvoxamine/chemistry , Humans , Membrane Potentials/drug effects , Membrane Potentials/physiology , Phenylalanine/genetics , Potassium Channel Blockers/chemistry , Potassium Channels/metabolism , Transcriptional Regulator ERG , Tyrosine/genetics
18.
Eur J Pharmacol ; 450(3): 223-9, 2002 Aug 30.
Article in English | MEDLINE | ID: mdl-12208313

ABSTRACT

Fluvoxamine, a selective serotonin re-uptake inhibitor, is used as antidepressant/anxiolytic. The presence of a C=N double bond in the structure of fluvoxamine implies the existence of two geometric isomers: E- (trans) and Z- (cis), and suggests the hypothetical susceptibility of the molecule to photoisomerization. Clinically effective fluvoxamine is in its trans form. UVB (ultraviolet light, class B, wavelength range 290-320 nm) irradiation of aqueous solutions of fluvoxamine generated a photoproduct, which was isolated and analyzed by nuclear magnetic resonance (NMR) and mass spectrometry (MS), and identified as the cis isomer of fluvoxamine. This cis-isomer lost capacity to inhibit serotonin uptake, suggesting that light exposure might reduce the clinical efficacy of fluvoxamine. Alternatively, the photoproduct could be used as an inactive isomer in the studies of antidepressant mechanisms. Recent proposal suggests that antidepressants increase neurogenesis in the adult brain, whereas either an inhibitory or a stimulatory action of antidepressants on [(3)H]thymidine uptake in vitro has been attributed to their interaction with serotonergic mechanisms. Lower concentrations (i.e., 2 microM) of fluvoxamine and fluoxetine (another selective serotonin re-uptake inhibitor) stimulated [(3)H]thymidine uptake in mature, but inhibited it in immature cultures of rat cerebellar granule cells; the photoproduct was ineffective. A high concentration of fluvoxamine (i.e., 20 microM) but not the photoproduct was toxic to both immature and mature cultures. We suggest that a mechanism sensitive to fluvoxamine photoisomerization might be involved in the action of antidepressants on cell proliferation.


Subject(s)
Antidepressive Agents, Second-Generation/chemistry , Fluvoxamine/chemistry , Ultraviolet Rays , Animals , Animals, Newborn , Antidepressive Agents, Second-Generation/pharmacology , Antidepressive Agents, Second-Generation/radiation effects , Brain/cytology , Brain/ultrastructure , Cell Division/drug effects , Cells, Cultured , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Drug Stability , Fluoxetine/chemistry , Fluvoxamine/pharmacology , Fluvoxamine/radiation effects , In Vitro Techniques , Male , Photochemistry , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Stereoisomerism , Synaptosomes/drug effects , Synaptosomes/metabolism
19.
Naunyn Schmiedebergs Arch Pharmacol ; 366(2): 158-65, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12122503

ABSTRACT

We have used the whole-cell patch clamp technique to study the effects of the commonly used antidepressants sertraline, paroxetine, citalopram and fluvoxamine on the volume-regulated anion channel (VRAC) in endothelial cells. It was the purpose of the present experiments to investigate whether VRAC block is a general property of this group of selective serotonin reuptake inhibitors (SSRIs). At pH 7.4, all SSRIs induced a fast and reversible block of the volume-sensitive chloride current ( I(Cl,swell)), with an IC(50) value of 2.1+/-0.5 microM for sertraline, 2.7+/-0.2 microM for paroxetine, 12.3+/-1.4 microM for fluvoxamine and 27.7+/-2.8 microM for citalopram. The block was enhanced at more alkaline pH, indicating that it is mediated by the uncharged form. This study describes the effects of a variety of SSRIs on an anion channel. Our data reveal a potent block and suggest a hydrophobic interaction of high affinity between the uncharged SSRI and volume-regulated anion channels. We conclude that VRAC block is a general property of this pharmacological class of selective serotonin reuptake inhibitors.


Subject(s)
Chloride Channels/antagonists & inhibitors , Selective Serotonin Reuptake Inhibitors/pharmacology , Antidepressive Agents/pharmacology , Cells, Cultured , Citalopram/chemistry , Citalopram/pharmacology , Dose-Response Relationship, Drug , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Fluvoxamine/chemistry , Fluvoxamine/pharmacology , Humans , Hydrogen-Ion Concentration , Hypotonic Solutions/pharmacology , Inhibitory Concentration 50 , Membrane Potentials/drug effects , Paroxetine/chemistry , Paroxetine/pharmacology , Patch-Clamp Techniques , Pulmonary Artery/cytology , Sertraline/chemistry , Sertraline/pharmacology
20.
J Pharm Biomed Anal ; 23(2-3): 477-81, 2000 Aug 15.
Article in English | MEDLINE | ID: mdl-10933541

ABSTRACT

Eriochrome cyanine R (ECR) reacts with fluvoxamine (FXM) and fluoxetine (FXT) forming coloured ion-association compounds. The composition of the compounds, studied by spectrophometric methods showed that the molar ratio ECR:FXM = 1:2 and ECR:FXT = 1:2. The formation and extraction conditions of the compounds were established. The compounds were characterised by UV, VIS, and IR spectrometry. It was found that the compounds are insoluble in water but quantitatively extracted into buthanol. Under the optimal experimental conditions fluvoxamine and fluoxetine were determined in the range 2-40 microg/ml and 2-20 microg/ml, respectively. The relative standard deviation is about +/- 2%.


Subject(s)
Benzenesulfonates/chemistry , Coloring Agents/chemistry , Fluoxetine/analysis , Fluvoxamine/analysis , Selective Serotonin Reuptake Inhibitors/analysis , Fluoxetine/chemistry , Fluvoxamine/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet
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