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Pharmaceutical Research Apr 2024Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable...
Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.
BACKGROUND
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.
PURPOSE
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).
METHODS
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.
RESULTS
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 AUC 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.
CONCLUSIONS
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.
Topics: Venlafaxine Hydrochloride; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2C19; Genotype; Desvenlafaxine Succinate; Polymorphism, Genetic
PubMed: 38443631
DOI: 10.1007/s11095-024-03680-8 -
Environmental Science and Pollution... Feb 2024In this paper, we report a study concerning the quantification of new emerging pollutants in water as a request from the third European Watch List mechanism. The EU...
Determination of pollutants, antibiotics, and drugs in surface water in Italy as required by the third EU Water Framework Directive Watch List: method development, validation, and assessment.
In this paper, we report a study concerning the quantification of new emerging pollutants in water as a request from the third European Watch List mechanism. The EU Watch List compound was investigated by an internal method that was validated in terms of detection limits, linearities, accuracy, and precision in accordance with quality assurance criteria, and it was used to monitor several rivers from 11 Italian regions. The methodology developed was satisfactorily validated from 5 to 500 ng L for the emerging pollutants studied, and it was applied to different river waters sampled in Italy, revealing the presence of drugs and antibiotics. Rivers were monitored for 2 years by two different campaigns conducted in 2021 and 2022. A total of 19 emerging pollutants were investigated on 45 samples. The most detected analytes were O-desmethylvenlafaxine and venlafaxine. About azole compounds, sulfamethoxazole, fluconazole, and Miconazole were found. About antibiotics, ciprofloxacin and amoxicillin were found in three and one samples, respectively. Moreover, statistical analyses have found a significant correlation between O-desmethylvenlafaxine with venlafaxine, sulfamethoxazole with venlafaxine, and fluconazole with venlafaxine.
Topics: Water; Venlafaxine Hydrochloride; Desvenlafaxine Succinate; Water Pollutants, Chemical; Anti-Bacterial Agents; Fluconazole; Rivers; Italy; Sulfamethoxazole
PubMed: 38280169
DOI: 10.1007/s11356-024-32025-6 -
Journal of Chromatography. A Jan 2024Psychotropic medications are one of the most prescribed pharmaceuticals in the world. Given their frequent detection and ecotoxicity to the no-target organism, the...
Psychotropic medications are one of the most prescribed pharmaceuticals in the world. Given their frequent detection and ecotoxicity to the no-target organism, the emission of these medications into environments has gradually draw attention. The study developed a sensitive and reliable analytic method to simultaneously investigate 47 psychotropic medications in four matrices: wastewater, surface water, activated sludge, and sediment by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). These 47 target analytes include 24 antidepressants, 17 antianxiety drugs, 5 anticonvulsants, and 1 relevant hormone. Solid phase extraction (SPE) was employed to extract analytes from water-phase samples. Ultrasonic Solvent Extraction method with Enhanced Matrix Removal clean-up (USE-EMR) was utilized to extract target compounds from solid-phase samples, which requires more straightforward and convenient procedures than previous methods. The extraction recoveries of all analytes ranged from 80 % to 120 % in these four sample matrices. In this study, The limit of quantitation for 47 psychotropic medications were 0.15 ng/L (estazolam) to 2.27 ng/L (lorazepam), 0.08 ng/L (desvenlafaxine) to 2 ng/L (mianserin), 0.22 ng/g (dry weight, dw) (nordiazepam) to 3.65 ng/g (dw) (lorazepam), and 0.07 ng/g (dw) (carbamazepine) to 2.85 ng/g (lorazepam), in wastewater, surface water, sludge, and sediment, respectively. In addition, the developed method was employed to analyse actual samples in two wastewater treatment plants and their receiving rivers. Carbamazepine, escitalopram, clozapine, desvenlafaxine, diazepam, lamotrigine, sertraline, temazepam, and venlafaxine were nearly ubiquitous in all matrices. Moreover, this study indicated that the inadequate removal efficiencies of psychotropic medications in wastewater treatment plants (WWTPs) had resulted in a persistent discharge of these contaminants from human sources into environments.
Topics: Humans; Tandem Mass Spectrometry; Wastewater; Chromatography, Liquid; Sewage; Liquid Chromatography-Mass Spectrometry; Lorazepam; Desvenlafaxine Succinate; Water; Psychotropic Drugs; Solid Phase Extraction; Water Pollutants, Chemical; Carbamazepine; Chromatography, High Pressure Liquid
PubMed: 38171065
DOI: 10.1016/j.chroma.2023.464627 -
Clinical Pharmacology and Therapeutics May 2024In 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...
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.
Topics: Aged; Humans; Cyclohexanols; Cytochrome P-450 CYP2D6; Depression; Desvenlafaxine Succinate; Genotype; Phenotype; Venlafaxine Hydrochloride
PubMed: 38284409
DOI: 10.1002/cpt.3162 -
Nanomedicine (London, England) 2024Desvenlafaxine (DES) in conventional dosage forms shows initial burst release after oral administration, leading to exaggeration of its side effects. These side effects...
Desvenlafaxine (DES) in conventional dosage forms shows initial burst release after oral administration, leading to exaggeration of its side effects. These side effects can be overcome by a sustained-release dosage form using the chemically inert, low-melting-point lipid Compritol 888 ATO, as it reduces initial burst release. The potential of DES-loaded solid lipid nanoparticles (DES-SLNs) synthesized by ultrasonication-assisted hot-melt encapsulation to modify the release of DES was investigated. The entrapment efficiency of DES-SLNs was 65.90% with the release profile showing a sustained-release behavior achieving 81% cumulative release within 16 h without initial burst release. DES-SLNs are a potential carrier for sustained release of water-soluble antidepressant drugs such as DES.
Topics: Desvenlafaxine Succinate; Nanoparticles; Drug Liberation; Delayed-Action Preparations; Fatty Acids; Drug Carriers; Antidepressive Agents; Particle Size; Lipids; Humans; Drug Compounding
PubMed: 38593058
DOI: 10.2217/nnm-2023-0229 -
Therapeutic Drug Monitoring Apr 2024This study presents the case of a 19-year-old woman who attempted suicide by ingesting 11.25 g of venlafaxine (V). She was admitted to the hospital with severe...
BACKGROUND
This study presents the case of a 19-year-old woman who attempted suicide by ingesting 11.25 g of venlafaxine (V). She was admitted to the hospital with severe biventricular dysfunction, progressing to cardiac arrest requiring extracorporeal circulatory life support for 11 days. The pharmacokinetics of venlafaxine during impaired cardiac output and the effect of its active metabolite, the O-desmethylvenlafaxine (ODV), are currently not very well understood.
METHODS AND RESULTS
Serum concentrations of V and ODV were monitored twice daily for 3 weeks. The maximum concentrations of venlafaxine and ODV were at 14 hours after ingestion, with 29,180 mcg/L for V and 5399 mcg/L for ODV. Half-lives increased, requiring 2 weeks to eliminate the drug. The left ventricular ejection fraction significantly improved when V + ODV was below 1000 mcg/L and remained altered until the ODV concentrations were lower than 400 mcg/L.
CONCLUSIONS
This report, with complete elimination kinetic of V and ODV in a monodrug intoxication, provides information about the modification of pharmacokinetics in the case of an overdose managed by extracorporeal circulatory life support, the cardiac toxicity of ODV, and the value of the toxic threshold for the active moiety.
Topics: Female; Humans; Young Adult; Cardiotoxicity; Desvenlafaxine Succinate; Stroke Volume; Teaching Rounds; Venlafaxine Hydrochloride; Ventricular Function, Left
PubMed: 38158602
DOI: 10.1097/FTD.0000000000001167