Metabolite O-desmethylvenlafaxine Research Articles

Field-deployable pencil lead-based electrochemical cell for the determination of the emerging contaminant and antidepressant drug venlafaxine in wastewater

Screening and quantification of emerging contaminants in water is of enormous relevance due to its scarcity and harmful effects on aquatic life and human health. We present a simple and cost-effective electrochemical cell for determination of the antidepressant venlafaxine, an emerging contaminant included in the EU Watch List 2022. The cell consists of pencil leads used as electrodes and a microcentrifuge tube. Modification of the working electrode with carbon nanomaterials improved the signal. Cell-related parameters (e.g., type of pencil leads or electroactive area) as well as experimental (e.g., pH, accumulation potential and time, and scan rate) were thoroughly optimized. The adsorptive nature of venlafaxine process allowed the use of adsorptive stripping square wave voltammetry methodology to increase the sensitivity. Under optimized variables, a linear range from 0.8 to 10 μmol L-1, with a correlation coefficient of 0.996 and a sensitivity of 1.48 μmol L-1, a LOD of 0.4 μmol L-1 and a RSD of 2.4 % were achieved. Selectivity was also studied, especially with respect to the main metabolite o-desmethylvenlafaxine. The methodology distinguishes its signal from that of the main compound, allowing its determination. A similar linear range was obtained for the metabolite, with a LOD of 0.6 μmol L-1. The platform developed was applied for venlafaxine quantification in spiked wastewaters from the Febros plant in Portugal, obtaining satisfactory recoveries. Furthermore, the versatility of pencil leads made it possible to combine them with modified paper for sampling and buffering in order to decentralize the determination, showing promising results.

Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.

Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

IntroductionThe selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet.ObjectivesWe performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression.MethodsFour databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal.ResultsHigh-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml.ConclusionVEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

C-Jun N-Terminal Kinases Inhibition: A New Approach to the Regulation of Venlafaxine Pharmacokinetics

The effect of the c-Jun N-terminal kinases (JNK) inhibitor 'IQ-1' on the pharmacokinetics of the antidepressant venlafaxine was studied. An acceleration of the metabolism of this psychotropic agent was revealed when a modifier of intracellular signal transduction was administered to experimental animals in vivo. The JNK blockade was accompanied by a decrease in the plasma level of the antidepressant without changes in the concentration of the pharmacologically active metabolite O-desmethylvenlafaxine. The results obtained indicate a modification of the pattern of venlafaxine biotransformation, involving a change in metabolic pathways with an increase in the formation of other metabolites, or a correction of its distribution in the body. The revealed properties of the JNK inhibitor can be used to develop fundamentally new approaches to improve the effectiveness of antidepressant therapy with venlafaxine within the framework of implementing the 'Strategy for Targeted Regulation of Xenobiotic Metabolism and Drug Pharmacokinetics'.

Accumulation and metabolization of the antidepressant venlafaxine and its main metabolite o-desmethylvenlafaxine in non-target marine organisms Holothuria tubulosa, Anemonia sulcata and Actinia equina

The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina is proposed. A 28-day exposure experiment (10 μg/L day) followed by a 52-day depuration period was conducted. The accumulation shows a first-order kinetic process reaching an average concentration of 49,125/54342 ng/g dw in H. tubulosa and 64,810/93007 ng/g dw in A. sulcata. Venlafaxine is considered cumulative (BCF > 2000 L/kg dw) in H. tubulosa, A. sulcata and A. equina respectively; and o–desmethylvenlafaxine in A. sulcata. Organism-specific BCF generally followed the order A. sulcata > A. equina > H. tubulosa. The study revealed differences between tissues in metabolizing abilities in H. tubulosa this effect increases significantly with time in the digestive tract while it was negligible in the body wall. The results provide a description of venlafaxine and o-desmethylvenlafaxine accumulation in common and non-target organisms in the marine environment.

Validated HPLC-UV method for determination of venlafaxine and its metabolite - o-desmethylvenlafaxine in human plasma

This paper describes a simple, rapid and cost-effective HPLC-UV method for the determination of venlafaxine and its active metabolite O-desmethylvenlafaxine in human plasma. Sample preparation is based on a liquid-liquid extraction procedure with a short extraction time. Prazosine hydrochloride was used as the internal standard. The HPLC separation was performed on a Supelcosil LC-CN column, using a mobile phase consisting acetonitrile : 25 mM phosphate buffer at pH 3,5 (15:85 v/v). The calibration curve is linear in the concentrations range of 25-1000 ng/mL, which is suitable for pharmacokinetic studies of venlafaxine hydrochloride following of dosing from 37.5 mg to 375.0 mg per day. The method was fully validated according to the international guidances,

Solar photocatalytic degradation of inherent pharmaceutical residues in real hospital WWTP effluents using titanium dioxide on a CPC pilot scale reactor

Hospital wastewaters (HWW) contain a complex mixture of pharmaceutical compounds that cannot be removed by conventional treatment processes. This study reports on the degradation of Pharmaceutical Active Compounds (PhACs) in hospital wastewater treatment plant (WWTP) secondary effluents using TiO2 and solar compound parabolic collector pilot plant. Inherent concentration loadings of pharmaceuticals in secondary wastewater were photocatalytically treated in a ‘’real-world’’ approach. Among the detected pharmaceuticals, amisulpride, venlafaxine and metabolite O-desmethyl venlafaxine, citalopram and carbamazepine occurred in all experimental runs. The analysis of the samples before and after the photocatalytic treatment was accomplished by solid phase extraction, followed by liquid chromatography-Orbitrap high-resolution mass spectrometry. Results showed that photocatalytic degradation of PhAcs followed first order kinetics. Catalyst loadings higher between 150 mgL−1 resulted in removal percentages higher than 73% with accumulative energy c.a. > 25 kJL−1 depending on the initial wastewater characteristics. For 200 mgL−1 catalyst loading pharmaceutical removal rate constants ranged between 0.018 and 0.039 LkJ−1 recorded for citalopram and venlafaxine, respectively. Photocatalytic treatment resulted also in the amelioration of the effluent quality physicochemical characteristics i.e. COD, BOD as well of the biodegradability index. The catalyst reusability was studied without any treatment for three consecutive cycles showing a significant efficiency decrease mainly between the first and the second cycle i.e. from 21% to 80% in the respective reaction constants. Finally, the effluent toxicity before and during the photocatalytic treatment was evaluated by Vibrio fischeri bioassay revealing that toxicity is sharply decreased leading to non-toxicity in the final treated effluents. Further studies on TiO2 photocatalytic applications should focus on the separation and regeneration of catalyst.

Multiple-reaction monitoring (MRM) LC–MS/MS quantitation of venlafaxine and its O-desmethyl metabolite for a preclinical pharmacokinetic study in rabbits

Preclinical pharmacokinetic (PK) studies in animal models during the formulation development phase give preliminary evidence and near clear picture of the PK behavior of drug and/or its dosage forms before clinical studies on humans and help in the tailoring of the dosage form according to the expected and requisite clinical behavior. The present work reports a first of its kind preclinical PK study on extended-release (ER) solid oral dosage forms of venlafaxine (VEN) in New Zealand White rabbits. The VEN is a highly prescribed and one of the safest and most effective therapeutic agents used in the treatment of different types of depression disorders worldwide. The multiple-reaction monitoring (MRM) LC–MS/MS method developed for this purpose demonstrated enough reliability in simultaneously quantitating VEN and its equipotent metabolite O-desmethylvenlafaxine (ODV) in rabbit plasma. The method described uses solid-phase extraction for sample preparation followed by an ultrafast LC–MS/MS analysis. The chromatographic separation was achieved isocratically with a predominantly polar mobile phase by employing RPLC. The triple quadrupole LC/MS/MS system operated in MRM mode used an ESI probe as an ion source in positive polarity. The validation results are within the permissible limits of US FDA recommendations and acceptance criteria for bioanalytical method validation.

Role of JNK in the Regulation of Xenobiotic Metabolizing Function of Hepatocytes.

We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.

Study of the distribution of antidepressant drugs in vitreous humor using a validated GC/MS method

Vitreous humor has become in recent years an important alternative biological fluid in forensic toxicological analysis especially for the investigation of cases where alcohol and drugs of abuse are involved but there is limited scientific information regarding the distribution of antidepressant drugs in this material. This work aimed to study the distribution of antidepressant drugs in vitreous humor and to estimate the blood/vitreous humor concentration ratios of these drugs. For this purpose, a GC/MS method for the simultaneous determination of 9 antidepressant drugs, namely amitriptyline, nortriptyline, citalopram, clomipramine, fluoxetine, maprotiline, mirtazapine, sertraline and venlafaxine, and 4 of their metabolites, namely desmethylmaprotiline, desmethylmirtazapine, desmethylsertraline, O-desmethylvenlafaxine, was developed and validated. The developed method includes solid-phase extraction followed by derivatization with Heptafluorobutyric Anhydride. For all analytes, LOD and LOQ were 1.50 and 5.00ng/mL, respectively, and the calibration curves were linear within the dynamic range of 5.00–500.0ng/mL (R2≥0.990). The absolute recovery was found to be ≥86.3 % for all analytes. The accuracy (%Er) was found to range between -6.58 and 6.18 %, whereas the precision (%RSD) was less than 10.9 % for all analytes. The developed method was successfully applied to vitreous humor samples from 43 blood positive cases for antidepressant drugs. Whenever antidepressant drugs were detected in blood, they were also detected in the respective vitreous humor samples. The vitreous humor/blood concentration ratios were also calculated and were found to range from 0.04–7.07. Citalopram, mirtazapine, and its metabolite desmethylmirtazapine as well as venlafaxine and its metabolite O-desmethylvenlafaxine were the most identified substances in these samples (n≥4) and their results were better statistically evaluated. Our results suggest that vitreous humor could be an appropriate matrix for the determination of antidepressants in postmortem toxicology.

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.

Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A.

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.

Influence of Zuojin Pill on the Metabolism of Venlafaxine in Vitro and in Rats and Associated Herb-Drug Interaction.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have a high likelihood of combination usage in patients with depression with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhP450s), especially on CYP2D6, whereas VEN undergoes extensive metabolism by CYP2D6. From this perspective, we investigated the influence of ZJP on the metabolism of VEN in vitro and in rats for the first time. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 μg/ml, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The area under drug concentration-time curve0-24 hour of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2 hours after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated clinical significance needed to be seriously considered. SIGNIFICANCE STATEMENT: Zuojin Pill, a commonly used Chinese herbal medicine, demonstrates significant inhibitory effects on hepatic metabolism and pharmacokinetics of venlafaxine in vitro and in rats mainly through suppression of CYP2D6 activity. The human pharmacokinetic interaction between Zuojin Pill and venlafaxine and its associated clinical significance needs to be seriously considered.

A Systematic Review on Analytical Methods to Determine Chiral and Achiral Forms of Venlafaxine and its Metabolite O-desmethylvenlafaxine

Background: Venlafaxine (VEN) is a bicyclic phenylethylamine derivative and possesses a marked structural difference from other antidepressant drugs present in the market. It works by eliciting the neurotransmitter action in CNS. It occurs in two enantiomeric forms i.e. R and S VEN. After the first pass metabolism, it gets metabolized into more active form O-desmethylvenlafaxine (ODV) which also exist in the enantiomeric forms. So it is important to develop a suitable analytical and bioanalytical method for the determination of VEN and its metabolite to quantify them accurately. Methods and Results: The current review summarizes methods to determine chiral and achiral forms of VEN and ODV. According to the literature, it is clear that most widely used method for the determination of VEN and ODV is liquid chromatography-mass spectroscopy, other methods used for routine analysis include UV spectroscopy, reverse phase high-performance liquid chromatography with PDA detector. For the determination of enantiomeric forms of VEN and ODV, different chiral columns have been utilized. Capillary electrophoresis with charged cyclodextrins is also used to determine the enantiomeric forms. Conclusion: Various analytical methods for determining VEN and its metabolite in different matrices have been discussed thoroughly in the present review.

Effect Of Chinese Herb Danzhi Xiaoyao Pills On Pharmacokinetics Of Venlafaxine In Beagles.

ObjectiveTo investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).MethodsSix beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0.ResultsThe Cmax of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC(0-∞) of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV Cmax of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC(0-∞) were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV Cmax of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC(0-∞) were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the Cmax and AUC(0-∞) of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of Cmax and AUC(0-∞) of ODV and NDV indicated a rise in plasma exposure.ConclusionDanzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.

Pharmacokinetics of venlafaxine in treatment responders and non-responders: a retrospective analysis of a large naturalistic database.

To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)). Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05. No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI - 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7mg/day, p= 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400ng/mL (13.04%) compared to patients with AM > 400ng/mL (8%) (p = 0.038). Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.

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.

Psychiatrics and selected metabolites in hospital and urban wastewaters: Occurrence, removal, mass loading, seasonal influence and risk assessment

The occurrence, removal, mass loading, seasonal influence and environmental risk assessment of nine psychiatric pharmaceuticals and four of their selected metabolites, were studied in one hospital and one urban wastewater treatment plant (WWTP) in Ioannina city, in northwestern Greece, providing information about the efficiency of the plants and their contribution into the final receiver's flow. Samples were collected from the influents and the effluents of the plants in different sampling campaigns, from July to December 2016. Analytical methodology was based on ultra-high performance liquid chromatography-Orbitrap high-resolution mass spectrometry, after solid-phase extraction through Oasis HLB cartridges. Concentrations in both WWTPs ranged between <LOQ and 1126.3 ng/L in the influents and between <LOQ and 1127.4 ng/L, in the effluents. Results indicated that venlafaxine and its metabolite O-desmethyl venlafaxine were the most frequently detected compounds in the influents and the effluents of both WWTPs. Metabolite to parent compound ratio ranged in the influents between 0.01 and 87.2 while in the effluents between 0.01 and 47.7. Based on mass loads in the influents, venlafaxine is consumed in high amounts (up to 67.1 mg/day/1000 inhab.), and consequently its metabolite O-desmethyl venlafaxine (up to 139.1 mg/day/1000 inhab.). Similarly to the influents, environmental emissions, were also higher for venlafaxine and O-desmethyl venlafaxine (10.1 and 13.3 mg/d/1000 inhab., respectively). Removal efficiencies in the hospital WWTP ranged from −100% to 98.9%, while in the city WWTP from −49.9% to 99.8%. Furthermore, an important outcome was the evaluation of the potential ecotoxicological risk, by means of risk quotients (RQs), where none of the target psychiatrics or their metabolites showed RQ above 1.