플루옥세틴

Positive

2.57

2.91

Waters Synapt G.2

Z-spray

formic acid (10nM)

177.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID7020635]

163.78 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

176.5 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

174.5 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Liver test abnormalities have been reported to occur rarely in patients on fluoxetine (less than 1%), and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on fluoxetine. The onset of injury is usually within 2 to 12 weeks and the pattern of serum enzyme elevations is usually hepatocellular, but convincing cases of mixed and cholestatic injury have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

The most common adverse effects reported by adults include insomnia, nausea, diarrhea, anorexia, dry mouth, headache, drowsiness, anxiety, nervousness, yawning, bruising, seizures, bleeding (rarely), hyperhidrosis, induction of mania, rare activation of suicidal ideation and behavior (especially in teenagers), weight gain/loss, decreased orgasm (anorgasmia and ejaculation latency), muscle weakness, tremors, and pharyngitis.

Well absorbed from the GI tract following oral administration. Oral bioavailability is estimated to be at least 60-80%. Peak plasma concentrations occur within 6-8 hours following a single oral administration of a 40 mg dose. The oral solution and delayed-release capsule are bioequivalent. Food does not affect the systemic bioavailability of fluoxetine but it delays the absorption by 1-2 hours (not clinically significant). Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations.

Fluoxetine is rarely lethal in monotherapy overdose. However, when taken with alcohol, it may cause ataxia and respiratory depression. The drug may cause serotonin syndrome (clinical constellation of changes in mental status, autonomic instability, and neuromuscular abnormalities) when taken in excessive amounts or combined with other agents that increase serotonin levels.

Fluoxetine is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

Symptoms of overdose include agitation, restlessness, hypomania, and other signs of CNS excitation. The most frequent side effects include: nervous system effects such as anxiety, nervousness, insomnia, drowsiness, fatigue or asthenia, tremor, and dizziness or lightheadedness; GI effects such as anorexia, nausea, and diarrhea; vasodilation; dry mouth; abnormal vision; decreased libido; abnormal ejaculation; rash; and sweating. Withdrawal symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory changes and hyperactivity.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

fluoxetine

Prozac®

Antidepressants

3

less-DILI-concern drugs

◉ Summary of Use during Lactation

◈ What is fluoxetine?

Fluoxetine

Pharmaceutical

Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions.

Fluoxetine has known human metabolites that include p-Trifluoromethyl phenol, Norfluoxetine, and (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[methyl-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]amino]oxane-2-carboxylic acid.

Limited data from animal studies suggest that fluoxetine may undergo first-pass metabolism may occur via the liver and/or lungs. Fluoxetine appears to be extensively metabolized, likely in the liver, to norfluoxetine and other metabolites. Norfluoxetine, the principal active metabolite, is formed via <i>N</i>-demethylation of fluoxetine. Norfluoxetine appears to be comparable pharmacologic potency as fluoxetine. Fluoxetine and norfluoxetine both undergo phase II glucuronidation reactions in the liver. It is also thought that fluoxetine and norfluoxetine undergo <i>O</i>-dealkylation to form <i>p</i>-trifluoromethylphenol, which is then subsequently metabolized to hippuric acid. Route of Elimination: The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The S-enantiomer is eliminated more slowly and is the predominant enantiomer present at steady state. Half Life: 1-3 days [acute administration]; 4-6 days [chronic administration]; 4-16 days [norfluoxetine, acute and chronic administration].

01K63SUP8D

FLUOXETINE

Established Pharmacologic Class [EPC] - Serotonin Reuptake Inhibitor

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Fluoxetine is a Serotonin Reuptake Inhibitor. The mechanism of action of fluoxetine is as a Serotonin Uptake Inhibitor.

FLUOXETINE

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake.

Compounds that specifically inhibit the reuptake of serotonin in the brain.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2D6.

The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain.

Fluoxetine is primarily eliminated in the urine.

The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg.

The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg.