Venlafaxine Concentrations Research Articles

Combine Effect of Vitamin C and venlafaxine on the Amino Acid Content of Saccharomyces cerevisiae

In this study, Saccharomyces cerevisiae (NRLLY-12632) was grown in YPD medium containing different concentrations of venlafaxine, (RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl] cyclohexanol. To counteract the effect of venlafaxine, vitamin C were added to the growth medium of S. cerevisiae, and amino acids content were investigated by HPLC. It was observed that, the amount of amino acids in S. cerevisiae grown in YPD medium, containing 100, 200, 300, 400 and 500 ppm venlafaxine were compared with the control, the amounts of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, histidine, isoleucine, leucine, lysine, phenylalanine, proline, threonine, tyrosine and valine increased (p<0.05), glutamic acid, glutamine, methionine, serine and tryptophan levels were decreased p<0.05). With the addition of vitamin C to the growth medium containing venlafaxine, all the amino acids concentrations get close to the control group. From these findings, it can be said that the negative effect of venlafaxine on S. cerevisiae is reduced by the addition of vitamin C to the medium.

Electrochemical determination venlafaxine at NiO/GR nanocomposite modified carbon paste electrode

The electro-oxidation of venlafaxine (VEN) was investigated at a carbon paste electrode, the modified electrode by NiO/graphene reduce (GR) nanocomposite. The structure and morphological aspects of the nanocomposite were approved using FE-SEM, EDAX, and FT-IR. The electrode reaction process was a diffusion-controlled one and the electrochemical oxidation involved two electrons transferring and two protons participating. Under the optimized conditions, the electro-oxidation peak currents were linearly dependent on the concentration of VEN in the concentration range from 1.0- 40.0 μM with the limit of detection (S/N=3) as 0.05 μM. The proposed method has been successfully applied in the electrochemical quantitative determination of VEN content in real samples and the determination, results could meet the requirement of the quantitative determination.

Venlafaxine and O-desmethylvenlafaxine serum levels are positively associated with antidepressant response in elder depressed out-patients

Background Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR). Methods 52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR. Results Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100–400 ng/mL) and a subsequent decrease of AR at higher serum levels. Discussion This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL

Multiple Organ Failure and Refractory Cardiogenic Shock due to Venlafaxine Intoxication, Successfully Treated with Veno-Arterial Extracorporeal Life Support

Venlafaxine has critical side effects from arrhythmias to cardiogenic shock after toxic dose ingestion. We report a case of venlafaxine intoxication with Multiple Organ Failure (MOF) treated with Veno-Arterial Extracorporeal Life Support (VA-ECLS). A 60-year old male with a history of chronic depression ingested 72 tablets of prolonged-release venlafaxine hydrochloride 75 mg (total 5400 mg). Initial EKG showed broadened QRS complexes and Transthoracic Echocardiography (TTE) revealed diffuse ventricular hypokinesia with Left Ventricular Ejection Fraction (LVEF) of 15% for which dobutamine infusion was started. Due to persistent refractory cardiogenic shock and MOF, a Medos® Deltastream® VA-ECLS was surgically implanted in our intensive care unit. On day 1, toxicology analysis found plasma concentrations of venlafaxine 3.2mg/L and its metabolite desmethylvenlafaxine at 0.92 mg/L. At day 6, we performed a weaning trial, enabling ECLS removal. Motion defect of anteroseptal and inferolateral walls was also noticed. EKGs showed a shorten R wave in the anteroseptal territory leading to the potential diagnosis of underlying ischemic cardiomyopathy. The patient was extubated at day-10 and discharged for cardiology unit at day-17. At day-20, cardiac magnetic resonance imaging showed no sign of ischemia and TTE parameters were normalized. This is the first report of refractory cardiogenic shock and MOF due to venlafaxine intoxication treated with VA-ECLS. The main objective of ECLS is to restore cardiac output especially when ventricular failure is refractory to inotropes. Our experience suggests that MOF secondary to refractory cardiogenic shock should quickly prompt the implantation of a VA-ECLS in venlafaxine critical overdose.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio)

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 μg/L, 10 μg/L, 100 μg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 μg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 μg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 μg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 β hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 μg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine.

PurposeThe purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo.MethodsThe mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague–Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry.ResultsWe observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine.ConclusionVonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.

Therapeutic Drug Monitoring of Venlafaxine and Impact of Age, Gender, BMI, and Diagnosis

AbstractDepression is a common mental disorder affecting more than 264 million people in the world and 5.1% of the Slovak population. Although various antidepressant approaches have been used; still, about 40% of patients do not respond to a first-choice drug administration and one third of patients do not achieve total remission. Therapeutic drug monitoring (TDM) is a method used for quantification and interpreting the drug concentrations in plasma in order to optimize the pharmacotherapy. The aim of this study was to measure the plasma concentrations of venlafaxine, the fourth most prescribed antidepressant in Slovakia, as well as its active metabolite and interpret them with the relevant patients’ characteristics.The study was of retrospective nature and 28 adult patients in total were included. The concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) in plasma were quantified using the validated UHPLC-MS/MS method. The effects of potential influencing factors were evaluated by a multivariate linear regression model.Only 39% of patients reached the venlafaxine active moiety concentrations within the recommended therapeutic range. Plasma concentrations were dependent on age, gender, and duration of the therapy. Venlafaxine metabolism expressed as a metabolite-to-parent concentrations ratio was influenced by a combination of age, gender, and body mass index (BMI). We did not observe any significant difference in plasma concentrations between the patients with a single and recurrent diagnosis of depression. Combining variables made an additive effect on plasma concentrations, for example, active moiety plasma concentrations were higher in older women. In contrast, drug metabolism was higher in older men and men with lower BMI. TDM of venlafaxine is recommended in clinical practice, especially in the elderly when beginning the pharmacotherapy.

Venlafaxine poisoning-induced severe hypoglycemia in a non-diabetic patient: a case report

Abstract Introduction: Venlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) used to treat major depressive episodes and anxiety. The risk of hypoglycemia is mentioned in the Summary of Product Characteristics (SmPC) of venlafaxine in the “warnings and precautions” section in diabetic patients. This effect appears neither in the “adverse reactions” nor in the “overdose” section. We herein report a case of severe hypoglycemia with coma in relation to venlafaxine poisoning. Case Report: A 35-year-old non-diabetic obese woman (BMI, 29 kg/m2) was found unconscious a few hours after ingesting venlafaxine and bromazepam in a suicide attempt. Vital signs on day 1 were as follows: Glasgow Coma score of 7, blood pressure of 99/66 mmHg and heart rate of 100/min. Electrocardiogram showed no abnormality. She was admitted to the intensive care unit. Due to sustained hypoglycemia [0.5 g/L (day1); 0.41 g/L (day2); 0.8 to 1.20 (day3)], she received continuous intravenous 10% glucose infusion for 3 days to normalize blood glucose. Plasma venlafaxine concentration was 11.7 times the upper the limit of therapeutic dose range (UTDR) on day 2 and reached the therapeutic dose range (TDR) on day 6. Plasma bromazepam concentration was 6.7 times UTDR on day 3 and reached TDR on day 8. Alternative etiologies of hypoglycemia were excluded, i.e. hypoglycemic sulfonamide, insulin poisoning, insulinoma, and disease of the adrenal gland, liver and thyroid. She was transferred to a psychiatric unit after one week. Discussion: Impairment of blood glucose homeostasis is rarely described with venlafaxine. In our patient, hypoglycemia appeared to be correlated with plasma venlafaxine concentrations and may be explained by increased insulin sensitivity, considering her obesity. Conclusion: Healthcare professionals should be aware of hypoglycemia induced by venlafaxine or other SNRIs in non-diabetic patients.

Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

The Influence of Combined CYP2D6 and CYP2C19 Genotypes on Venlafaxine and O-Desmethylvenlafaxine Concentrations in a Large Patient Cohort.

The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population. Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference. The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%. The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.

Pregnancy exposure to venlafaxine—Therapeutic drug monitoring in maternal blood, amniotic fluid and umbilical cord blood and obstetrical outcomes

BackgroundFor treatment with psychotropic drugs during pregnancy, extended therapeutic drug monitoring is recommended for individual therapy adjustment. We measured venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and active moiety, AM (sum of VEN+ODV) concentrations in maternal serum, amniotic fluid and umbilical cord blood. MethodsConcentrations of VEN, ODVEN and AM were measured in nine mother-infant pairs at time of delivery; in five cases, amniotic fluid samples were available. Concentrations are reported as median values, first (Q1) and third (Q3) quartiles and ranges. Penetration ratio was calculated by dividing concentrations of VEN, ODVEN and AM in amniotic fluid and umbilical cord blood by maternal serum concentrations. ResultsMedian daily dosage of venlafaxine was 75 mg (range 37.5–225 mg). There were no significant correlations between daily dose, maternal serum, umbilical cord blood and amniotic fluid concentrations. Median penetration ratio into amniotic fluid was 2.5 (range 0.56–4.48). Median penetration ratio into fetal circulation was 1.05 (range 0.62–2.08). Median concentration of AM was 223.8 ng/mL, range 33.9–338.0 ng/mL (maternal serum), 789.0 ng/mL, range 309-1052.5 ng/mL (amniotic fluid) and 291.0 ng/mL, range 21.1–448.4 ng/mL (cord blood). DiscussionVEN, ODVEN and AM concentrations in maternal serum, amniotic fluid and umbilical cord blood indicate that the fetus might have been exposed to relatively high concentrations throughout pregnancy. High concentrations in amniotic fluid indicate an increased penetration into and/or accumulation within amniotic fluid and a decreased elimination out of amniotic fluid. Findings indicate that fetal in-utero exposition to venlafaxine is higher compared to other antidepressants.

The effect of the antidepressant venlafaxine on gene expression of biotransformation enzymes in zebrafish (Danio rerio) embryos.

The effect of venlafaxine, a pharmaceutical commonly found in aquatic environment, was analyzed on non-target organism, Danio rerio (Hamilton, 1822). D. rerio embryos were treated by two different concentrations of venlafaxine: either concentration relevant in aquatic environment (0.3 μg/L) or concentration that was two orders of magnitude higher (30 μg/L) for the evaluation of dose-dependent effect. Time-dependent effect was rated at 24, 96, and 144 h post-fertilization (hpf). For gene expression, genes representing one of the phases of xenobiotic biotransformation (0 to III) were selected. The results of this study showed that the effect of venlafaxine on the zebrafish embryos is the most evident at hatching (96 hpf). At this time, the results showed a downregulation of gene expression in each phase of biotransformation and in both tested concentrations. In contrast, an upregulation of most of the genes was observed 144 hpf for both tested venlafaxine concentrations. The study shows that venlafaxine can affect the gene expression of biotransformation enzymes in D. rerio embryos even in the environmentally relevant concentration and thus disrupt the process of biotransformation. Moreover, the pxr regulation of genes seems to be disrupted after venlafaxine exposure in dose- and time-dependent manner.

ASSESSMENT OF THE POTENTIAL GENOTOXICITY AND CARDIAC TERATOGENICITY OF VENLAFAXINE ON EMBRYOS OF PREGNANT BLACK MICE

Background: Depression during pregnancy is a very common problem worldwide, so the possibility of intake antidepressant medications during pregnancy is high. In Egypt, about 60% of pregnant women experience someforms of antenatal depression.The most widely prescribed antidepressants worldwide are Selective serotonin and serotonin–norepinephrine reuptake inhibitors (SSRIs and SNRIs).The mechanism of action is poorly understood but in general, these drugs act by blocking the serotonin and/or norepinephrine transporters.Aim: The aim of this study is to investigate the effect of venlafaxine- one of the most widely prescribed SSRI (Selective serotonin reuptake inhibitors) on DNA, and also study its possible teratogenic effect on cardiac development.Methods: The present study was carried out on fifty pregnant black mice (C57BL/6).The mice were randomly assigned to one of two groups: a control and venlafaxine-treated groups receiving (3mg, 10mg, 30mg and 100mg/kg/day). The fetuses were dissected for the evaluation of their cardiac structure. The micronucleus test was used to detect the ability of venlafaxine to induce DNA damage.Results: The present work showed that administration of increasing concentrations of venlafaxine resulted in significant increase in the incidence of embryo heart anomalies in black mice as VSD, pulmonary trunk dilatation and right ventricle enlargement as compared to the control group. Also, this study showed an increase in the frequency of micronuclei in the blood of the adult mice after exposure to increasing dose of venlafaxine.Conclusions: Physicians should make a proper decision regarding prescription of SSRI in general and venlafaxine, in particular, to treat depression during pregnancy weighing the risks and benefits for both mother and fetus.

Cytochrome P450-mediated inhibition of venlafaxine metabolism by trimipramine.

The aim of this study was to ensure patients' safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample. Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann-Whitney U test with a significance level of 0.05. Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012). Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug-drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients' safety.

Influencing Factors and Transformation Mechanism of Venlafaxine Degradation by UV

As a member of antidepressants, venlafaxine degradation by UV was investigated in this study. The influence of initial concentration of venlafaxine, pH value, and water quality on venlafaxine removal were studied. The results showed that venlafaxine degradation fitted the pseudo-first-order kinetics model. The reaction rate increased with the decrease of venlafaxine concentration. It was found that the highest removal rate of venlafaxine occurred at pH 10. The degradation of venlafaxine involves direct photolysis and self-sensitized photolysis caused by hydroxyl radical (·OH) and singlet oxygen (1O2). Moreover, the direct photolysis played a dominant role in the venlafaxine removal. Water matrix also affected venlafaxine degradation. The results indicated that the degradation rate of venlafaxine in the secondary effluent was lower than that in the ultrapure water. Inorganic anions (Br-, Cl-, NO3-, and NO2-) impacted venlafaxine removal, and the inhibition of NO2- was stronger than others'. Both humic acid and fulvic acid also inhibited venlafaxine decomposition. UPLC-MS/MS was used to perform full scan to identify intermediates of venlafaxine degradation. Five degradation pathways were proposed:①demethylation; ②deamination; ③sequential hydroxylation of aromatic rings; ④ring opening of cyclohexane; ⑤low-molecular-weight acid transformation. In addition, 87% of the N element in the molecules were transformed into inorganic ions (ammonium ions and nitrate ions).

Ionic liquid-coated magnetic SiO2@Fe3O4 nanocomposite for temperature-assisted solid-phase extraction of venlafaxine

A temperature-assisted solid-phase extraction method was developed for the extraction of venlafaxine prior to its spectrofluorimetric determination. Ionic liquid modified Fe3O4 (IL@SiO2@Fe3O4) nanoparticles were prepared, characterized and used as the sorbent. A simple, one-step, rapid and nature-friendly method was used for the preparation of iron oxide nanoparticles using cinnamon extract. The synthesized Fe3O4 was characterized using X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The SEM images showed that the synthesized Fe3O4 nanoparticles have an approximately spherical structure with the sizes in the range of 30–60 nm. The synthesized Fe3O4 nanoparticles were coated with three ionic liquids: 1-butyl-3-methylimidazole hexafluorophosphate, 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide and ethyl-3- methylimidazolium ethyl-1 sulfate. The ionic liquid-coated magnetic nanoparticles were used for the extraction of venlafaxine from aqueous solutions. The highest extraction efficiency was obtained using 1-butyl-3-methylimidazole hexafluorophosphate-coated nanoparticles. The extracted venlafaxine was then determined spectrofluorimetrically at λex and λem of 261 and 301 nm, respectively. Under the optimal conditions, the relation between venlafaxine concentration and fluorescence intensity was linear in the range of 0.003–3.00 mg L−1 of the initial solution. The limit of detection for the determination of venlafaxine was found to be 0.001 mg L−1. The presented method was applied for the determination of venlafaxine in real samples with satisfactory results.

Pharmacokinetic correlates of venlafaxine: associated adverse reactions.

To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.

Impact of fullerenes in the bioaccumulation and biotransformation of venlafaxine, diuron and triclosan in river biofilms

A huge variety of organic microcontaminants are presently detected in freshwater ecosystems, but there is still a lack of knowledge about their interactions, either with living organisms or with other contaminants. Actually, carbon nanomaterials like fullerenes (C60) can act as carriers of organic microcontaminants, but their relevance in processes like bioaccumulation and biotransformation of organic microcontaminants by organisms is unknown. In this study, mesocosm experiments were used to assess the bioaccumulation and biotransformation of three organic microcontaminants (venlafaxine, diuron and triclosan) in river biofilms, and to understand how much the concomitant presence of C60 at environmental relevant concentrations could impact these processes. Results indicated that venlafaxine exhibited the highest bioaccumulation (13% of the initial concentration of venlafaxine in water), while biotransformation was more evident for triclosan (5% of the initial concentration of triclosan in water). Furthermore, biotransformation products such as methyl-triclosan were also present in the biofilm, with levels up to 42% of the concentration of accumulated triclosan. The presence of C60 did not involve relevant changes in the bioaccumulation and biotransformation of microcontaminants in biofilms, which showed similar patterns. Nevertheless, the study shows that a detailed evaluation of the partition of the organic microcontaminants and their transformation products in freshwater systems are important to better understand the impact of the co-existence of others microcontaminants, like carbon nanomaterials, in their possible routes of bioaccumulation and biotransformation.

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.

CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P<0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n=269), CYP2D6*9-10/null (n=17), CYP2D6*41/null (n=30) and CYP2D6null/null (n=95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.