플루옥세틴

Fluoxetine (range 20-252 ug/L) was detected in five of the nine infants from whom /plasma/ samples were collected, and norfluoxetine (range 17-187 ug/L) was detected in seven of the nine infants. Mothers of these infants were being treated with fluoxetine for depression. The highest of these concentrations was about 70% of the maternal plasma concentrations. The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% national level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.

If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.

Elevated plasma phenytoin concentrations resulting in symptoms of toxicity have been reported when fluoxetine was used concurrently with phenytoin; caution and close monitoring are suggested.

Because of the possibility that fluoxetine may inhibit the metabolism of astemizole, leading to increased blood levels and risk of cardiac arrhythmias, including torsades de pointes, concurrent use is not recommended.

Both increased and decreased lithium concentrations, as well as some cases of lithium toxicity, have been reported with concomitant fluoxetine use; close monitoring of lithium concentrations is recommended.

Concurrent use of fluoxetine with monamine oxidase (MAO) inhibitors may result in confusion, agitation, restlessness, gastrointestinal symptoms, hyperpyretic episodes, severe convulsion, hypertensive crises, the serotonin syndrome, or death. Concurrent use is contraindicated, and at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of fluoxetine. However, because of the long half-lives of fluoxetine and its active metabolite, at least 5 weeks (approximately 5 half-lives of norfluoxetine) should elapse between discontinuation of fluoxetine and initiation of therapy with an MAO inhibitor. Deaths following the initiation of an MAO inhibitor shortly after stopping fluoxetine administration have been reported.

For more Interactions (Complete) data for FLUOXETINE HYDROCHLORIDE (19 total), please visit the HSDB record page.

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.

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 and norfluoxetine are distributed into milk. Limited data indicate that concentrations of the drug and this metabolite in milk are about 20-30% of concurrent plasma concentrations.

To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg/kg/day) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 hr dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal.

IDENTIFICATION: Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant agent. It is soluble in: water, methanol, chloroform and insoluble in hexane, ethyl acetate and benzene. HUMAN EXPOSURE: Main risks and target organs: Fluoxetine is safer in overdose than most other classes of antidepressants. In overdosage, most patients experience only mild neurological and gastroenterological symptoms; significant cardiovascular toxicity is unusual. The serotonergic effects of fluoxetine may be enhanced by combination with other antidepressants, monoamine oxidase inhibitors, carbamazepine or lithium and produce a life-threatening serotoninergic syndrome comprising hyperthermia, tremor and convulsions. Summary of clinical effects: Drowsiness, tremor, headache, blurred vision, dizziness, restlessness, and rarely, seizures and coma. Nausea, vomiting, abdominal pain. Bradycardia, mild hypertension or hypotension. Contraindications: Absolute: Hypersensitivity to fluoxetine. Coadministration of sumatriptan, non-specific monoamine oxidase inhibitors and B-specific monoamine oxidase inhibitors. Relative: Combination therapy with A-specific monoamine oxidase inhibitors or other antidepressants. Pregnancy or lactation. Routes of entry: Oral: Fluoxetine is administered orally. Absorption by route of exposure: Fluoxetine hydrochloride is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing from 6 to 8 hours after oral administration. The systemic bioavailability is greater than 85 % and does not appear to be affected by food. Distribution by route of exposure: Fluoxetine is widely distributed throughout the body. Plasma protein binding is 94 %. Biological half-life by route of exposure: Fluoxetine has a relatively long and highly variable half-life ranging from 1 to 4 days after a single dose and averaging nearly 70 hours; patients receiving high doses over long periods of time may exhibit prolonged elimination half-lives. The half-life of its active metabolite, norfluoxetine, is about 7 to 9 days. Metabolism: Fluoxetine is extensively metabolized in the liver to a desmethyl metabolite, norfluoxetine, which has activity similar to fluoxetine. Peak plasma concentrations of the active metabolite, norfluoxetine, occur around 76 hours after ingestion. Elimination and excretion: The primary route of elimination appears to be further hepatic metabolism to inactive metabolites which are conjugated and then excreted in the urine. Mode of action: Toxicodynamics: Fluoxetine is a potent inhibitor of serotonin re-uptake by Central Nervous System neurones and may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Pharmacodynamics: Fluoxetine specifically inhibits neuronal re-uptake of serotonin, thus increasing the concentration of the serotonin at the synapse and reinforcing of serotonergic neuronal transmission. Fluoxetine has little effect on other neurotransmitters. Fluoxetine has no direct effect on the heart. Carcinogenicity: Human studies: there is no evidence of carcinogenicity in patients taking fluoxetine. Teratogenicity: Human studies: a study of 128 women exposed to fluoxetine during the first trimester showed no increase in major fetal malformations. It is not known, however, if the drug is a human teratogen. A neonate whose mother had been taking fluoxetine during most of her pregnancy suffered tachypnea, emesis, continuous crying, irritability, tremor and increased muscle tone; the symptoms resolved within 96 hours. Fluoxetine and norfluoxetine are excreted in breast milk. The effects on the infant are uncertain. Caution should be exercised when fluoxetine is administered to a nursing mother. Interactions: Drug interactions with fluoxetine have been reported with L-tryptophan, L-dopa; monoamine oxidase inhibitors: selegiline, tranylcypromine; tricyclic antidepressants; selective serotonin re-uptake inhibitors: trazodone, zimeldine; benzodiazepines: alprazolam, diazepam; buspirone, lithium, anticonvulsants: carbamazepine, phenytoin, valproate; pentazocine, dextromethorphan, fenfluramine, calcium channel blockers, benztropine, cyproheptadine, clarithromycin. Cannabis, ethanol and LSD. At least 14 days should elapse between discontinuing a MAO-inhibiting antidepressant and introducing fluoxetine. Conversely, because of the long half-life of fluoxetine and its metabolite, norfluoxetine, it is recommended that at least 5 weeks should elapse between discontinuation of fluoxetine and the introduction of a MAO inhibitor. Main adverse effects: The major adverse effects reported with therapeutic doses of fluoxetine are primarily those of headache, insomnia, nausea, and nervousness. Less common adverse effects include tremors, sweating, dry mouth, anxiety, drowsiness, and diarrhea. ANIMAL/PLANT STUDIES: Carcinogenicity: Animal studies: fluoxetine was not carcinogenic in rats and mice at doses ten times the recommended daily dose for 24 months. Teratogenicity: Animal studies: in rats, fluoxetine and norfluoxetine cross the placenta and distribute within the fetus during the periods of organogenesis and postorganogenesis. Levels in fetal tissue are approximately half the corresponding maternal concentrations. Fluoxetine does not impair the fetal growth in rats or rabbits at doses nine and eleven times the maximum daily human dose respectively. Mutagenicity: In vitro: fluoxetine and norfluoxetine did not show mutagenicity in the Ames test. There was no induction of sister-chromatid exchange in the bone marrow of the Chinese Hamster.

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.

/SIGNS AND SYMPTOMS/ In general, overdosage of fluoxetine may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects. Animal studies and case reports in humans indicate that possible effects of overdosage include agitation, restlessness, hypomania, insomnia, tremor, and other signs of CNS excitation; nausea and vomiting; and tachycardia and/or increased blood pressure.

/CASE REPORTS/ To report the development of a possible serotonin syndrome in a patient taking buspirone and fluoxetine. A 37-year-old white man taking fluoxetine 20 mg/d for generalized anxiety disorder developed confusion, diaphoresis, incoordination, diarrhea, and myoclonus after buspirone was added to the drug regimen. Serotonin syndrome is a potentially lethal condition of serotonin hyperstimulation, which may develop rapidly or over the course of several weeks. Symptoms of serotonin syndrome typically occur following additions or increases of serotonin-enhancing drugs. Although buspirone has variable effects on post- and presynaptic 5-HT1A receptors that may reduce the risk of serotonin syndrome when administered as a single agent, it may cause an adverse reaction when given with other serotonergic drugs. Symptoms consistent with serotonin syndrome may develop with the concurrent administration of buspirone and fluoxetine.

/CASE REPORTS/ A possible case of serotonin syndrome in a 45 yr old depressed woman resulting from the administration of 20-40 mg/day of fluoxetine hydrochloride (Prozac), 10-20 mg 2 times/day of tranylcypromine sulfate (Parnate), and 500 mg/day of tryptophan to treat refractory depression is described. It was likely that the combination of prozac, parnate, and tryptophan increased the availability of serotonin in the CNS to produce the syndrome. The patient died and the cause of death was listed as toxic encephalopathy with multisystem failure caused by neuroleptic malignant syndrome.

/CASE REPORTS/ Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10-17 yr old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury.

For more Human Toxicity Excerpts (Complete) data for FLUOXETINE HYDROCHLORIDE (11 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Fluoxetine hydrochloride

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Tonic-clonic seizures occurred in 5 of 6 dogs given a toxic dose of fluoxetine orally; the seizures ceased immediately after IV administration of diazepam. In these dogs, the lowest plasma fluoxetine concentration at which seizures occurred reportedly was only twice the maximum plasma concentration reported in humans receiving 80 mg of the antidepressant daily during long-term therapy. Single large oral doses of fluoxetine reported do not cause QT- or PR-interval prolongation or widening of the QRS complex in dogs, although tachycardia and an increase in blood pressure have occurred.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Gravid Sprague-Dawley rats were administered 5.62 mg/kg Fluoxetine HCl by gavage beginning day 6 or 7 of pregnancy and ending the day of birth. A control group received distilled water during the lactating period (birth to day 21). At birth Fluoxetine exposed pups showed a statistically higher frequency of skin hematomas when compared to water controls (Fluoxetine: 63/189, Water: 2/113, X2 = 34.61, p less than .001).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No evidence of teratogenicity was found in studies in rats and rabbits receiving fluoxetine doses that were 1.5 and 3.6 times, respectively, the MRHD (maximum recommended human dose) on a mg/sq m basis. However, an increase in stillbirths and pup deaths during the first postpartum week was seen in rats given 1.5 times the MRHD on a mg/sq m basis during gestation or 0.9 times the MRHD on a mg/sq m basis during gestation and lactation.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No evidence of adverse effects on fertility was seen in rats given fluoxetine doses of 0.9 to 1/5 times the MRHD (maximum recommended human dose) on a mg/sq m basis.

/GENOTOXICITY/ Fluoxetine and norfluoxetine have shown no genotoxic effects in the bacterial mutation assay; DNA repair assay in cultured rat hepatocytes; mouse lymphoma assay; or in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

The half-life of fluoxetine reportedly is prolonged (to approximately 4-5 days) after administration of multiple versus single doses, suggesting a nonlinear pattern of drug accumulation during long-term administration.

Following a single oral dose of fluoxetine in healthy adults, the elimination half-life of fluoxetine reportedly averages approximately 2-3 days (range: 1-9 days) and that of norfluoxetine averages about 7-9 days (range: 3-15 days).

The mean half-life /for fluoxetine/ was 6.6 vs 2.2 days ... for patients with cirrhosis vs normal volunteers.

The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome p450 (CYP) involved in this metabolic pathway. The kinetics of Ne formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single-enzyme Michaelis-Menten equation (mean Km=32 umol/L +/- 7 umol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25 umol/L and 100 umol/L and 3-hydroxylation of tolbutamide at 250 micromol/L (r1=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100 umol/L. S-mephenytoin (SMP) (a CYP2C19 substrate) at high concentration and sulfaphenazole (SUL) (a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The reaction was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (triacetyloleandomycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100 umol/L) was greater in PM livers than in EM livers (73 % vs 45 %, P < 0.01) when the microsomes were precoincubated with SUL plus TAO. Cytochrome p450 CYP2C9 is likely to be a major CYP isoform catalyzing fluoxetine N-demethylation in human liver microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP2C19 may play a more important role in this metabolic pathway at high substrate concentration.

The exact metabolic fate of fluoxetine has not been fully elucidated. The drug appears to be metabolized extensively, probably in the liver, to norfluoxetine and several other metabolites. Norfluoxetine (desmethylfluoxetine) the principal metabolite, is formed by N-demethylation of fluoxetine, which may be under polygenic control. The potency and selectivity of norfluoxetine's serotonin-reuptake inhibiting activity appear to be similar to those of the parent drug. Both fluoxetine and norfluoxetine undergo conjugation with glucuronic acid in the liver, and limited evidence from animals suggests that both the parent drug and its principal metabolite also undergo O-dealkylation to form p-trifluoromethylphenol, which subsequently appears to be metabolized to hippuric 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].

FLUOXETINE HCL

Serotonin Uptake Inhibitors [MoA]; Serotonin Reuptake Inhibitor [EPC]

FLUOXETINE HYDROCHLORIDE

Serotonin Uptake Inhibitors [MoA]; Serotonin Reuptake Inhibitor [EPC]

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.

Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of fluoxetine in humans has not been fully elucidated to date, but at least 60-80% of an oral dose appears to be absorbed. However, the relative proportion of an oral dose reaching systemic circulation unchanged currently is not known. Limited data from animals suggest that the drug may undergo first-pass metabolism and extraction in the liver and/or lung following oral administration. In these animals (beagles), approximately 72% of an oral dose reached systemic circulation unchanged. Food appears to cause a slight decrease in the rate, but not the extent of absorption of fluoxetine in humans.

Distribution of fluoxetine and its metabolites into human body tissues and fluids has not been fully characterized. Limited pharmacokinetic data obtained during long term administration of fluoxetine to animals suggest that the drug and some of its metabolites, including norfluoxetine, are widely distributed in body tissues, with highest concentrations occurring in the lungs and liver. The drug crosses the blood-brain barrier in humans and animals. In animals, fluoxetine: norfluoxetine ratios reportedly were similar in the cerebral cortex, corpus striatum, hippocampus, hypothalamus, brain stem, and cerebellum 1 hr after administration of single dose of the drug.

In order to confirm embryonic/fetal exposure to fluoxetine and/or metabolites, dissection and whole-body autoradiographic techniques were utilized to determine the placental transfer and fetal distribution in 12 and 18 day pregnant Wistar rats 1, 4, 8, and 24 hr following a single oral 12.5 mg/kg dose of (14)C fluoxetine. On gestation Days 12 (organogenesis) and 18 (postorganogenesis), peak concentrations of radiocarbon occurred 4-8 hr after dose administration in the placenta, embryo/fetus, amniotic fluid, and maternal kidney, brain, and lung, and declined slightly at 24 hr postdose. Maternal lung contained the highest tissue concentration of radiocarbon at all time points. Placenta and maternal brain, kidney, and liver contained moderate levels of radioactivity, while embryonic/fetal tissue, amniotic fluid, and maternal plasma contained low levels of radioactivity. Mean fetal concentrations of radiocarbon at 4, 8, and 24 hr on gestation Day 18 were higher than mean embryonic concentrations on Day 12 of gestation. Analytical characterization of radioactivity indicated that combined fluoxetine and norfluoxetine concentrations accounted for 63-80% of the total radiocarbon concentrations in embryonic/fetal tissue. Results indicated that embryonic/fetal and maternal tissue levels of fluoxetine were greatest at early time points and declined with time, while norfluoxetine tissue levels were highest at the 24 hr time point. Whole-body autoradiographic techniques demonstrated that radioactivity associated with (14)C fluoxetine and/or its metabolites traversed the placenta and distributed throughout the 18 day fetus 4 hr following dose administration. Visual and quantitative evaluations of the autoradiograms indicated that the highest fetal concentrations of radiocarbon were associated with brain and thymus. Results from these studies indicate that fluoxetine and norfluoxetine traverse the placenta and distribute within the embryo/fetus during the periods of organogenesis and postorganogenesis and confirm embryonic/fetal exposure of parent and metabolite in previous negative rat teratology and reproductive studies.

Elimination: Renal: 80% excreted in the urine (11.6% fluoxetine, 7.4% fluoxetine glucuronide, 6.8% norfluoxetine, 8.2% norfluoxetine glucuronide, >20% hippuric acid, 46% other); Biliary: Approximately 15% in the feces; In dialysis--Not dialyzable because of high protein binding and large volume of distribution.

For more Absorption, Distribution and Excretion (Complete) data for FLUOXETINE HYDROCHLORIDE (6 total), please visit the HSDB record page.