The Tissue-Specific Eco-Exposome: Differential Pharmaceutical Bioaccumulation and Disposition in Fish among Trophic Positions.

Though bioaccumulation of pharmaceuticals by aquatic organisms continues to receive scientific attention, the internal disposition of these contaminants among different tissue compartments of fish species has been infrequently investigated, particularly among fish at different trophic positions. We tested a human to fish biological read-across hypothesis for contaminant disposition by examining tissue-specific accumulation in three understudied species, longnose gar (Lepisosteus osseus; piscivore), gizzard shad (Dorosoma cepedianum; planktivore/detritivore), and smallmouth buffalo (Ictiobus bubalus; benthivore), from a river influenced by municipal effluent discharge. In addition to surface water, fish plasma, and brain, gill, gonad, liver, and lateral muscle fillet tissues were analyzed via isotope dilution liquid chromatography tandem mass spectrometry. Caffeine and sucralose, two common effluent tracers, were quantitated at low micrograms per liter levels in surface water, while an anticonvulsant, carbamazepine, was observed at levels up to 37 ng/L. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and primary metabolites were detected in at least one tissue of all three species at low micrograms per kilogram concentrations. Within each species, brain and liver of select fish contained the highest levels of SSRIs compared to plasma and other tissues, which is generally consistent with human tissue disposition patterns. However, we observed differential accumulation among specific tissue types and species. For example, mean levels of sertraline in brain and liver tissues were 13.4 µg/kg and 1.5 µg/kg in gizzard shad and 1.3 µg/kg and 7.3 µg/kg in longnose gar, respectively. In contrast, smallmouth buffalo did not consistently accumulate SSRIs to detectable levels. Tissue-specific eco-exposome efforts are necessary to understand mechanisms associated with such marked bioaccumulation and internal dispositional differences among freshwater fish species occupying different trophic positions. Environ Toxicol Chem 2024;43:1894-1902. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 µg/mL), Cmax (368.07 ± 0.23 µg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Protective role of ellagic acid and taurine against fluoxetine induced hepatotoxic effects on biochemical and oxidative stress parameters, histopathological changes, and gene expressions of IL-1ß, NF-κB, and TNF-α in male Wistar rats.

PURPOSES: Hepatic bioactivation of fluoxetine (FXN) could increase free radicals' generation provoking hepatotoxicity. Therefore, the protective effects of ellagic acid (EA) and taurine (TAU) treatments against fluoxetine-induced liver damage in rats were examined. MATERIALS AND METHODS: Sixty four male Wistar rats were randomly assigned to 8 groups (n = 8). Group (1) Control, group (2) FXN, group (3) FXN + EA, group (4) FXN + TAU, group (5) FXN + EA + TAU, group (6) EA, group (7) TAU, and group (8) EA + TAU. Then, the serum and tissue parameters of the oxidative stress were examined. KEY FINDINGS: FXN significantly raised serum MDA, protein carbonyl, lipid profile, ALT, AST, ALP, total bilirubin, serum IL-1ß; and gene expressions of IL-1ß, NF-κB, and TNF-α. Moreover, it significantly decreased HDL-C, ferric reducing antioxidant power (FRAP), catalase activity, vitamin C, and SOD activity in the liver compared to group 1. When compared to group 2, EA and TAU treatment dramatically increased antioxidant capacity and lowered hepatotoxic biochemical markers and cellular inflammation. Results also showed a protective effect of treatment against oxidative damage caused by hepatocytes' cytoarchitecture. SIGNIFICANCE: Our study concluded the beneficial effects of EA and TAU on FXN-induced hepatotoxicity. These effects were derived from free radical scavenging properties and the anti-inflammatory effects related to IL-1ß, NF-κB, and TNF-α gene expression inhibition.

Neurochemical and behavioral effects of fluoxetine on midazolam induce dependence in an animal model of addiction.

In the present study we have monitored effects of repeated coadministration of fluoxetine with midazolam; a benzodiazepine (CNS depressant). It is the primary drug of choice for procedural sedation, preoperative sedation, and in emergency departments. Repeated administration of this drug is reported to have abuse potential and may cause this by increasing dopaminergic neurotransmission. Since an important role of serotonin is there in the pathophysiology of anxiety and addiction, administration of midazolam may involve altered 5-HT metabolism as well. Present study was designed to monitor effects of repeated administration of fluoxetine with midazolam. Effects of fluoxetine and midazolam coadministration were monitored on motor activities in familiar and novel environments, hot plate test, forced swim test, conditioned place preference test and levels of dopamine, 5-HT and their metabolites. Both midazolam (2.5mg/kg) and fluoxetine (1mg/kg) were administered orally for 12 days. Conditioned place preference test was performed on day 13. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study show attenuation of midazolam-induced reinforcement upon repeated co-administration of fluoxetine. These could be implicated to increased therapeutic utility of midazolam and related benzodiazepines.

P-glycoprotein mediates the pharmacokinetic interaction of olanzapine with fluoxetine in rats.

Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) and Mdr1a/b gene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (Cmax, 44.1 ± 5.1 ng/mL in the combination group vs 9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC0-t, 235.8 ± 22.7 h × ng/mL in the combination group vs 47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination group vs 49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased the in vivo exposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cells in vitro as well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine.

Factors associated with fluoxetine and norfluoxetine plasma concentrations and clinical response in Mexican patients with mental disorders.

Over the last few years, fluoxetine has been one of the most prescribed medications for the treatment of diverse psychiatric conditions in Mexico. Fluoxetine therapeutic effect is consequence of the joint action of the parent drug and its active metabolite, norfluoxetine. However, the clinical efficacy of fluoxetine, can be affected due to diverse factors, such as drug-drug interactions and the large interindividual variability in the pharmacokinetics of this drug. The aim of this study was to determine the factors associated with variability in plasma concentrations of fluoxetine and norfluoxetine and its association with the therapeutic response. Fluoxetine and norfluoxetine plasma concentrations were quantified by liquid chromatography in 81 Mexican patients with mental disorders; 25% of the patients had no medication adherence and 40% were below the reference range of fluoxetine plus norfluoxetine plasma concentrations. The results showed that concentrations can be affected by fluoxetine metabolism caused by CYP2D6 phenotype and the concomitant administration of olanzapine. Furthermore, CYP3A5 and CYP2C19 phenotype were associated with lower anxiety and depression control during treatment with fluoxetine. This study can be a starting point to elucidate the causes of fluoxetine variable response in Mexican patients with mental disorders, as well as to detect and support medication adherence.

Prediction of Fluoxetine and Norfluoxetine Pharmacokinetic Profiles Using Physiologically Based Pharmacokinetic Modeling.

Fluoxetine is a selective serotonin reuptake inhibitor that is metabolized to norfluoxetine by cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A4. A physiologically based pharmacokinetic model for fluoxetine and norfluoxetine metabolism was developed to predict and investigate changes in concentration-time profiles according to fluoxetine dosage in the Korean population. The model was developed based on the Certara repository model and information gleaned from the literature. Digitally extracted clinical study data were used to develop and verify the model. Simulations for plasma concentrations of fluoxetine and norfluoxetine after a single dose of 60 or 80 mg fluoxetine were made based on 1000 virtual healthy Korean individuals using the SimCYP version 19 simulator. The mean ratios (simulated/observed) after a single administration of 80 mg fluoxetine for maximum plasma concentration, area under the plasma concentration-time curve, and apparent clearance were 1.12, 1.08, and 0.93 for fluoxetine; the ratios of maximum plasma concentration and area under the plasma concentration-time curve were 1.08 and 1.08, respectively, for norfluoxetine, indicating that the simulated concentration-time profiles of fluoxetine and norfluoxetine fitted the observed profiles well. The developed model was used to predict plasma fluoxetine and norfluoxetine concentration-time profiles after repeated administrations of fluoxetine in Korean volunteers. This physiologically based pharmacokinetic model could provide basic understanding of the pharmacokinetic profiles of fluoxetine and its metabolite under various situations.

Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

[Investigation of the distribution of (±)-N-methyl-3-phenyl-3-(para-trifluoromethyl) phenoxypropylamine hydrochloride in the body of warm-blooded animals]. / Izuchenie raspredeleniya (±)-N-metil-3-fenil-3-(para-triftormetil) fenoksipropilamina gidrokhlorida v organizme teplokrovnykh zhivotnykh.

THE AIM OF THE STUDY: Was to investigate the distribution of (±)-N-methyl-3-phenyl-3-(para-trifluoromethyl) phenoxypropylamine hydrochloride (fluoxetine) in the body of warm-blooded animals. For the experiments, Wistar rats were used. Fluoxetine was isolated from animal organs and bio-liquids by liquid-liquid extraction. Thin layer chromatography, UV spectrophotometry, and high performance liquid chromatography were used for identification and quantification. Techniques for isolating fluoxetine from urine, blood, intestinal contents, kidneys, and liver samples using liquid-liquid extraction are presented. Methods for identification and quantitative determination of fluoxetine in extracts by thin layer chromatography, UV spectrophotometry, and high performance liquid chromatography are described. The greatest amount of fluoxetine was found in the kidneys - 12.94±2.18 mg/100 g, the small intestine with contents - 9.50±1.90 mg/100 g and liver - 9.28±1.37 mg/100 g.

How precise is quantitative prediction of pharmacokinetic effects due to drug-drug interactions and genotype from in vitro data? A comprehensive analysis on the example CYP2D6 and CYP2C19 substrates.

Drug-drug interactions (DDI) and genomic variation (PG) can lead to dangerously high blood and tissue concentrations with some drugs but may be negligible with other drugs. Using a quantitative metaanalysis, we analyzed on the example of CYP2D6 and CYP2C19 substrates, how well the effects of DDI and PG can be predicted by in vitro methods. In addition, we analyzed the quantitative effect of prototypic inhibitors of the two enzymes in relation to their genetic deficiency. More than 600 published studies were screened which compared either human pharmacokinetics with and without comedication, or which compared human pharmacokinetics of deficient with extensive metabolizers, or which assessed metabolism by in vitro approaches. With human liver microsomes, the in vitro to in vivo agreement of fractional clearances was reasonably high if loss of substrate was quantified in the in vitro assays performed with and without enzyme specific inhibitors. Also a generally very high correlation between the clinical pharmacokinetic effects of inherited deficiency and inhibition by drug-drug interactions could be demonstrated. Most cases of poor correlation were explained by the lack of CYP2D6 versus CYP2C19 specificity of fluoxetine or by a poor knowledge of the quantitative contribution of the metabolic pathways if metabolite formation was quantified in the in vitro assays. The good correspondence of the in vitro data with clinical DDI and clinical PG studies may be a good basis for future application of these methods in drug development and drug therapy.

Simultaneous quantification of vortioxetine, fluoxetine and their metabolites in rat plasma by UPLC-MS/MS.

In this study, a specific and quick ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was fully developed and validated for simultaneous measurement of the rat plasma levels of vortioxetine (VOR), Lu AA34443 (the major metabolite of VOR), fluoxetine and its metabolite norfluoxetine with diazepam as the internal standard (IS). After a simple protein precipitation with acetonitrile for sample preparation, the separation of the analytes were performed on an Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 µm) column, with acetonitrile and 0.1% formic acid in water as mobile phase by gradient elution. The detection was achieved on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via an electrospray ionization source. Good linearity was observed in the calibration curve for each analyte. The data of precision, accuracy, matrix effect, recovery and stability all conformed to the bioanalytical method validation of acceptance criteria of US Food and Drug Administration recommendations. The newly developed UPLC-MS/MS method allowed simultaneous quantification of VOR, fluoxetine and their metabolites for the first time and was successfully applied to a pharmacokinetic study in rats.

Serotonin induces Arcadlin in hippocampal neurons.

The monoamine hypothesis does not fully explain the delayed onset of recovery after antidepressant treatment or the mechanisms of recovery after electroconvulsive therapy (ECT). The common mechanism that operates both in ECT and monoaminergic treatment presumably involves molecules induced in both of these conditions. A spine density modulator, Arcadlin (Acad), the rat orthologue of human Protocadherin-8 (PCDH8) and of Xenopus and zebrafish Paraxial protocadherin (PAPC), is induced by both electroconvulsive seizure (ECS) and antidepressants; however, its cellular mechanism remains elusive. Here we confirm induction of Arcadlin upon stimulation of an N-methyl-d-aspartate (NMDA) receptor in cultured hippocampal neurons. Stimulation of an NMDA receptor also induced acute (20 min) and delayed (2 h) phosphorylation of the p38 mitogen-activated protein (MAP) kinase; the delayed phosphorylation was not obvious in Acad-/- neurons, suggesting that it depends on Arcadlin induction. Exposure of highly mature cultured hippocampal neurons to 1-10 µM serotonin for 4 h resulted in Arcadlin induction and p38 MAP kinase phosphorylation. Co-application of the NMDA receptor antagonist d-(-)-2-amino-5-phosphonopentanoic acid (APV) completely blocked Arcadlin induction and p38 MAP kinase phosphorylation. Finally, administration of antidepressant fluoxetine in mice for 16 days induced Arcadlin expression in the hippocampus. Our data indicate that the Arcadlin-p38 MAP kinase pathway is a candidate neural network modulator that is activated in hippocampal neurons under the dual regulation of serotonin and glutamate and, hence, may play a role in antidepressant therapies.

Pharmacogenetics and therapeutic drug monitoring of fluoxetine in a real-world setting: A PK/PD analysis of the influence of (non-)genetic factors.

This work presents the GnG-PK/PD-AD study-a pharmacokinetics/pharmacodynamics (PK/PD) analysis of the impact of genetic and nongenetic factors on the treatment with the antidepressant fluoxetine (FLU)-with a focus on potential biomarkers. Seventy-nine depressed patients treated with FLU were recruited and clinically characterized in the scope of the study. Clinical outcomes, including remission and antidepressant adverse effects were assessed by means of the Hamilton Depression Rating Scale and the Antidepressant Side-Effect Checklist, respectively. Patients were submitted to therapeutic drug monitoring of FLU and norfluoxetine and genotyping of the CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes. A multivariate analysis was used to evaluate the impact of genetic and nongenetic factors on the drug plasma concentrations and clinical outcomes and to identify potential biomarkers. Genetically determined CYP2D6 activity was found to be a predictor of FLU and norfluoxetine concentrations (p < .05). In turn, genetic and nongenetic factors related to CYP2D6 and P-glycoprotein were found as potential biomarkers of the clinical outcomes of FLU (p < .05). Specifically, the potential of the CYP2D6 to be inhibited by drug-induced phenoconversion was associated with a higher severity of depression (p < .05). Moreover, ABCB1 TTT-haplotype was favorable to better clinical outcomes with FLU (higher likelihood of remission and lower severity of adverse effects; p < .05). The potential of the P-glycoprotein to be inhibited by drug-induced phenoconversion was also related to a worse tolerability profile (higher severity and number of adverse effects; p < .05). Lastly, the presence of nervous system comorbidities was associated with a higher severity of adverse effects and aging and the female gender with a higher severity of depression and lower probability of remission (p < .05). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Metabolomic Investigations of the Temporal Effects of Exposure to Pharmaceuticals and Personal Care Products and Their Mixture in the Eastern Oyster (Crassostrea virginica).

The eastern oyster (Crassostrea virginica) supports a large aquaculture industry and is a keystone species along the Atlantic seaboard. Native oysters are routinely exposed to a complex mixture of contaminants that increasingly includes pharmaceuticals and personal care products (PPCPs). Unfortunately, the biological effects of chemical mixtures on oysters are poorly understood. Untargeted gas chromatography-mass spectrometry metabolomics was utilized to quantify the response of oysters exposed to fluoxetine, N,N-diethyl-meta-toluamide, 17α-ethynylestradiol, diphenhydramine, and their mixture. Oysters were exposed to 1 µg/L of each chemical or mixture for 10 d, followed by an 8-d depuration period. Adductor muscle (n = 14/treatment) was sampled at days 0, 1, 5, 10, and 18. Trajectory analysis illustrated that metabolic effects and class separation of the treatments varied at each time point and that, overall, the oysters were only able to partially recover from these exposures post-depuration. Altered metabolites were associated with cellular energetics (i.e., Krebs cycle intermediates), as well as amino acid metabolism and fatty acids. Exposure to these PPCPs also affected metabolic pathways associated with anaerobic metabolism, osmotic stress, and oxidative stress, in addition to the physiological effects of each chemical's postulated mechanism of action. Following depuration, fewer metabolites were altered, but none of the treatments returned them to their initial control values, indicating that metabolic disruptions were long-lasting. Interestingly, the mixture did not directly cluster with individual treatments in the scores plot from partial least squares discriminant analysis, and many of its affected metabolic pathways were not well predicted from the individual treatments. The present study highlights the utility of untargeted metabolomics in developing exposure biomarkers for compounds with different modes of action in bivalves. Environ Toxicol Chem 2020;39:419-436. © 2019 SETAC.

Experimental and Clinical Pharmacokinetics of Fluoxetine and Amitriptyline: Comparative Analysis and Possible Methods of Extrapolation.

The pharmacokinetics of two fluoxetine capsulated dosage forms and two amitriptyline tablet forms after a single oral intake was studied in dogs and healthy volunteers. High significant correlations were detected between plasma concentrations of fluoxetine (r=0.96, p<0.00001, n=11) and amitriptyline (r=0.78, p<0.0224, n=8) in dogs and volunteers. A correlation of medium strength (though insignificant) was detected between nortriptyline concentrations in the plasma of dogs and volunteers (r=0.69, p<0.199, n=5). The bioavailability parameters of the test drugs in dogs and volunteers did not differ. Similar trends of fluoxetine and amitriptyline pharmacokinetic parameters were revealed in volunteers and animals. Methods for extrapolation of experimental pharmacokinetics parameters of fluoxetine and amitriptyline obtained on dogs for humans are proposed and validated.

Increasing serotonin bioavailability in preweaned dairy calves impacts hematology, growth, and behavior.

Peripheral serotonin has been shown to regulate important physiological functions such as energy homeostasis and immunity, particularly in rodent and humans, but its role is poorly understood in livestock species. Herein, we tested the safety and effectiveness of increasing serotonin bioavailability in preweaned dairy calves by oral supplementation of a serotonin precursor (5-hydroxytryptophan, 5-HTP) or a serotonin reuptake inhibitor (fluoxetine, FLX). Bull Holstein calves (21 ± 2 d old; N = 24) were fed milk replacer (8 L/d) supplemented with either saline as control (CON, 8 mL/d, n = 8), FLX (40 mg/d, approx. 0.8 mg/kg; n = 8), or 5-HTP (90 mg/d, approx. 1.8 mg/kg; n = 8) for 10 consecutive days in a complete randomized block design. Heart rate (HR), respiration rate, rectal temperature, and health scores were recorded daily. Hip height and body weight were measured at d 1, 5, and 10 relative to initiation of supplementation. Blood samples were collected once before the supplementation period (d 1), during the 10-d supplementation period (daily), and during a 14-d withdrawal period (d 2, 3, 4, 7, and 14 relative to initiation of withdrawal). Cerebrospinal fluid and muscle tissue were collected from a subset of calves (n = 12) that were euthanized after the 10-d supplementation or 14-d withdrawal period. Whole blood serotonin concentrations increased in 5-HTP calves and decreased in FLX calves compared with CON (P < 0.001), indicating that serotonin bioavailability was increased in both groups. Whole blood serotonin concentrations of 5-HTP and FLX calves returned to CON levels after 7 d of withdrawal. All calves grew and were considered healthy throughout the study. In fact, calves fed 5-HTP had higher average daily gain compared with CON (0.87 vs 0.66 ± 0.12 kg/d, P = 0.05). Calves fed FLX had lower HR (P = 0.02) and greater red blood cells and hemoglobin counts on d 10 of supplementation compared with CON (P < 0.01). After the 14-d withdrawal period, FLX was not detected in circulation of FLX calves, but was still present in the muscle tissue. Our results demonstrate that manipulation of the serotonin pathway by supplementing FLX or 5-HTP is a feasible and safe approach in preweaned dairy calves; however, it takes more than 14 d for FLX to be completely withdrawn from the body.

Comparison of the accumulation and metabolite of fluoxetine in zebrafish larva under different environmental conditions with or without carbon nanotubes.

Few studies have focused on the influence of environmental conditions on the bioavailability of pollutants interacted with nanomaterials in organisms. In this study, we primarily compared the influence of multiwalled carbon nanotubes (MWCNTs) on the bioavailability of fluoxetine in zebrafish (Danio rerio) larva under different environmental conditions: natural organic matter (NOM) and salinity. The results showed that fluoxetine accumulated in the larvae and then transformed into the metabolite norfluoxetine, with the metabolic rates from 2.8 to 3.5. Following co-exposure to MWCNTs, the accumulation of fluoxetine and norfluoxetine were further enhanced, suggesting a superior carrier of MWCNTs for fluoxetine, especially the functional MWCNTs. The consistent increase in the fluoxetine and norfluoxetine accumulation highlights the bioavailability of absorbed fluoxetine on MWCNTs in zebrafish larvae. The presence of NOM promoted the accumulation of fluoxetine and norfluoxetine in zebrafish, but alleviated the carrier effects of MWCNTs, acting as a natural antidote. Salinity negatively influenced the bioavailability of fluoxetine in the larvae, and further reversed the enhancements caused by MWCNTs. These findings provide a new insight into the influence of environmental conditions on the interactions between nanomaterials and pollutants in organisms.

An in vivo evaluation of the ontogeny of stereoselective fluoxetine metabolism and disposition in lambs from birth to one year of age.

1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S-FX and R,S-norfluoxetine (R,S-NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus. Total body clearance (ClTB) did not significantly increase up to 33.6 ± 0.9 days, but significantly increased at 98.5 ± 2.0 days, with no further changes up to 397.3 ± 8.5 days. Up to 13.4 ± 0.8 days, the disposition of FX included Phase I metabolism to NFX and trifluoromethylphenol (TFMP), and renal elimination. At 32.9 ± 0.9 days, metabolism included Phase II conjugates of FX and NFX. Renal elimination of these compounds was low. 4. The elimination of FX increased in a non-linear manner during the first year in sheep. The metabolism and disposition of FX and NFX in plasma and urine were stereoselective and this appeared due to both stereoselective protein binding and metabolism.