Fluoxetine

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Fluoxetine
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Executive Summary Information

Compound Fluoxetine (Prozac)
Toxicities Phospholipidosis
Mechanisms Fluoxetine is a classic cationic amphiphilic compound that physically associates with phospholipids, causing intracellular sequestration and accumulation.
Comments Fluoxetine was selected as a standard for hepatic phospholipidosis with minimal additional complicating activities in the liver.
Feedback Contact Gold Compound Working Group (GCWG)
Fluoxetine
Fluoxetine.png


Identifiers
Leadscope Id LS-31040
CAS 54910-89-3
DrugBank DB00472
ChemSpider 3269
UNII 01K63SUP8D
ChEBI 5118
Pathway DBs
KEGG D00326
Assay DBs
PubChem CID 3386
ChEMBL 41
Omics DBs
Properties
ToxCast Accepted no
Toxic Effect Phospholipidosis
ToxBank Accepted yes
Approved on 2012-05-01
Target Selective serotinin reuptake inhibitor (SSRI),NMDA receptors containing the GluN2B
Toxicities Phospholipidosis


In Vivo Data ? Compound Assessment
Adverse Events ? Fluoxetine is associated with pulmonary phospholipidosis, hepatitis, and hepatic steatosis.

The lung and alveolar macrophages are prominent sites of phospholipidosis in vivo. Because phospholipidosis is generally confirmed by electron microscopy, which requires invasive tissue removal, the prevalence of phospholipidosis in humans may not be fully appreciated.

References:

-William H. Halliwell, “Cationic Amphiphilic Drug-Induced Phospholipidosis”, Toxicol Pathol (1997) 25: 53.
-Nakissa Sadrieh, “The Regulatory Challenges of Drug-induced Phospholipidosis”, ACPS meeting, APRIL 14, 2010

In many cases there is no clinical effect from the phospholipidosis, and the net effect of phospholipidosis may be to protect against other toxicities.

References:

-Mark Reasor and Sam Kacew Drug-Induced Phospholipidosis: Are There Functional Consequences? Experimental Medicine and Biology 2001 226(9) p825-830.

Reports from the FDA AERS database 2000-2011 for hepatobiliary adverse events. The most common is steatosis. Frequency of increased liver enzymes was 5 per 1000 patients and less than 0.3 per 1000 for hepatitis in clinical trials, though this may be an underestimation since onset of hepatitis can require an induction period of 1 month or more. Post marketing surveillance indicates a low frequency of liver injury (defined as increased bilirubin plus increased liver enzymes) of 0.7 cases per 100,000 patient-years of exposure, comparable to low-dose aspirin, when adverse events are normalized to exposure.

References:

-D. Capella, M. Bruguera, Figueras, and J.R. Laporte, “Fluoxetine-induced hepatitis: why is postmarketing surveillance needed?”, Eur J Clin Pharmacol (1999) 55: 545-546.
-M. Sabate, L. Ibanez, E. Perez, X. Vidal, M. Buti, X. Xiol, A. Mas, C. Guarner, M. Forne, R. Sola, J. Castellote, J. Rigau & J.-R. Laporte, “Risk of acute liver injury associated with the use of drugs: a multicentre population survey”, Aliment Pharmacol Ther (2007) 25, 1401–1409.

Reports from FDA AERS of cardiac adverse events. The most common are cardiac arrest and syncope (fainting). The reports of QT elongation and torsade de pointes are statistically significant.

Toxicity Mechanisms ? The phospholipidosis observations are consistent with the general mechanism of phospholipidosis caused by cationic amphiphilic drugs (CADs). DNA microarray studies indicate that fluoxetine and similar drugs alter lysosomal function and cholesterol levels.

References:

-Hiroshi Sawada, Kenji Takami, and Satoru Asahi , “A Toxicogenomic Approach to Drug-Induced Phospholipidosis: Analysis of Its Induction Mechanism and Establishment of a Novel in Vitro Screening System”, Toxicological Sciences, 2004 Volume 83, Issue 2, p 282-292.
Therapeutic Target ? Selective serotinin reuptake inhibitor (SSRI), partially through 5HT2C antagonism. Fluoxetine is an agonist against the sigma1-receptor and is active against the SLC33A3 cation transporter.

References:

-Zhu, HJ; Appel, DI; Gründemann, D.; Richelson, E.; Markowitz, J. S. Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action. Pharmacology Research 2012 65(4) p 491-496.

NMDA receptors containing the GluN2B, which are implicated in long-term memory potentiation.

References:

-Kiss, J.P.; Szasz, B.K.; Fodor, L.; Mike, A.; Lenkey, N.; Kurkó, D.; Nagy, J.; Vizi, E. S. GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine. Neurochem Int. 2012 60(2) p 170-176.

FDA and Label Information

The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products

This next url will perform a search in the FDA's system for all labels for products that contain Fluoxetine as an active ingredient.
FDA Label Search


PubMed references

The following resource link will perform a PubMed query for the terms " Fluoxetine " and "liver toxicity".
Fluoxetine Search

The following resource link will perform a PubMed query for the terms " Fluoxetine " and "cardio toxicity".
Fluoxetine Search

PK-ADME ? Compound Assessment
PK parameters ?
  • Dose = 20-80 mg/day (oral)
  • Cmax = 13 ug/L (fluoxetine + norfluoxetine after single 20 mg dose).
  • Steady state plasma concentration = 160-560 ug/L (fluoxetine + norfluoxetine after 30 days of 40 mg/kg dosing)
  • plasma half-life = 1-4 days, 7-15 days for norfluoxetine
  • 95% protein bound in plasma
  • Vd = 20-45 L/kg, with highest accumulation in lung lysosomes (i.e. phospholipidosis)

References:

-Christoph Hiemke, Sebastian Härtter, “Pharmacokinetics of selective serotonin reuptake inhibitors”, Pharmacology & Therapeutics 85 (2000) 11–28. NDA application data
Therapeutic window ? Not applicable
Metabolically activated ? Metabolite norfluoxetine (Seproxitine) is the N-demethylation product and is also active as an SSRI. There is no evidence for activation to a chemically reactive species.

References:

-Christoph Hiemke, Sebastian Härtter, “Pharmacokinetics of selective serotonin reuptake inhibitors”, Pharmacology & Therapeutics 85 (2000) 11–28.
-PubChem

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Rat

References:

-Lee, J.-H. et. al. Gene Expression profile analysis of genes in rat hippocampus from antideprressant treated rats using DNA microarray. BMC Neuroscience 2010 11:152.

Human

References:

-Little, K. Y.; Zhang, L.; Cook, E. Fluoxetine-induced alterations in human platelet serotonin transporter expression: serotonin transporter polymorphism effects J Psychiatry Neurosci. 2006 31(5) p 333–339.
-Hiroshi Sawada, Kenji Takami, and Satoru Asahi, “A Toxicogenomic Approach to Drug-Induced Phospholipidosis: Analysis of Its Induction Mechanism and Establishment of a Novel in Vitro Screening System”, Toxicological Sciences 83, 282–292 (2005).
-Paul Nioi, Brad K. Perry, Er-Jia Wang, Yi-Zhong Gu, and Ronald D. Snyder, “In Vitro Detection of Drug-Induced Phospholipidosis Using Gene Expression and Fluorescent Phospholipid–Based Method”, Toxicological Sciences 99(1), 162–173 (2007).
Proteomics profiles known. ? Human

References:

-Bayés, A.; Grant, S. G. N. Neuroproteomics: understanding the molecular organization and complexity of the brain Nature Reviews Neuroscience 2009 10, p 635-646
Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? Serotonin SERT transporter affinity Ki: 0.72 nM

References:

-Taber, M. T. et. al Neurochemical, pharmacokinetic, and behavioral effects of the novel selective serotonin reuptake inhibitor BMS-505130. Pharmacol Biochem Behav. 2005 Mar; 80(3):521-8.

Serotonin reuptake in human choriocarcinoma cells transfected with human transporter IC50: 9.4 nM

References:

-Mahaney, P.E. et al Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors. J Med Chem. 2008 Jul 10;51(13):4038-49.

Dopamine reuptake inhibition: 6 uM

References:

-Wong, D.T.; Robertson, D. W.; Bymaster F. P. Krushinski, J. H.; Reid, L. R. LY227942, an inhibitor of serotonin and norepinephrine uptake: biochemical pharmacology of a potential antidepressant drug. Life Sci. 1988;43(24):2049-57.

NMDA receptors containing the GluN2B, 10 uM

References:

-Kiss, J.P.; Szasz, B.K.; Fodor, L.; Mike, A.; Lenkey, N.; Kurkó, D.; Nagy, J.; Vizi, E. S. GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine. Neurochem Int. 2012 60(2) p 170-176.

5HT2c serotonin receptors in Xenopus oocytes: ~ 20 uM

References:

-Ni, Y. G. and Miledi, R. Blockage of 5HT2c serotonin receptors by fluoxetine (Prozac) Proc. Natl. Acad. Sci. USA 1997, 94, p 2036-2040.
Observed IC50 for in vitro cellular toxicity studies. ? In HepG2 cells, gene expression studies have used 8 µM fluoxetine for 24 h. Accumulation of fluorescently-labeled phospholipids is statistically significant after 24 h at 10 µM (3.7 x control), but not at 3 µM (1.2 x control) in CHO cells. MIC for toxicity was ~30 µM in CHO cells.

References:

-Paul Nioi, Brad K. Perry, Er-Jia Wang, Yi-Zhong Gu, and Ronald D. Snyder, “In Vitro Detection of Drug-Induced Phospholipidosis Using Gene Expression and Fluorescent Phospholipid–Based Method”, Toxicological Sciences 99(1), 162–173 (2007).
-Toshihiko Kasahara, Kazuo Tomita, Hiroyuki Murano, Tsuyoshi Harada, Keisuke Tsubakimoto, Takuo Ogihara, Syuhei Ohnishi, and Chihaya Kakinuma, “Establishment of an In Vitro High-Throughput Screening Assay for Detecting Phospholipidosis-Inducing Potential”, Toxicological Sciences 90(1), 133–141 (2006).
-Hiroshi Sawada, Kenji Takami, and Satoru Asahi, “A Toxicogenomic Approach to Drug-Induced Phospholipidosis: Analysis of Its Induction Mechanism and Establishment of a Novel in Vitro Screening System”, Toxicological Sciences 83, 282–292 (2005).

IC50 for cytotoxicity at 10 days: 

 Cardiac ES cells: 1.8 µM 
 NIH-3T3 fibroblasts: 4.8 µM

References:

-Kusakawa, S.; Yamauchi, J.; Miyamoto, Y; Sanbe, A. Tanoue, A., “Estimation of embryotoxic effect of fluoxetine using embryonic stem cell differentiation system” Life Sci 2008 83, p 871-877.

CYP2C19 Inhbition (R), (S), Racemic IC50 17, 67, 27 µM

References:

-Stresser, D. M. et al Differential Time- and NADPH-dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine Presented as a poster, Intl. Society of Xenobiotics 2008.

HERG channel block 1.5 uM

References:

-Paul, A. A.; Leishman, D. J.; Witchel, H. J.; Hancox, J. C. Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes. J Pharm Pharmacol. 2001 Dec;53(12):1671-8.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? Fluoxetine exhibited good stability at -20 and 5 degrees C, but was unstable at room temperature under the same conditions.

References:

-IA Binsumait, KA Hadidi, SA Raghib. Stability of fluoxetine in stored plasma, aqueous, and methanolic solutions determined by HPLC with UV detection. Pharmazie 2001, 56(4):311-313
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Fluoxetine hydrochloride observed water solubility: 4 mg/ml

References:

-Sigma Aldrich F132
  • Estimated intrinsic solubility : 5.6411e-2 mg/ml
  • Estimated solubility in pure water at pH 10.16: 0.1009 mg/ml
  • Estimated solubility in water at pH 7.4: 18.74 mg/ml

(Calculations performed using ACD/PhysChem v 12.0)

Solubility in DMSO 100 times buffer solubility. ? Fluoxetine hydrochloride > 5 mg/ml

References:

-Sigma Aldrich F132
Vessel binding properties. ?

References:

-
Vapor pressure. (Non-volatile) ? estimated vapor pressure:(25°C): 2.52E-005 mmHg (Calculation performed using EPI Suite v4.1)

Authors of this ToxBank wiki page

David Bower, Egon Willighagen
Retrieved from "http://wiki.toxbank.net/wiki/Fluoxetine"
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