5-HT

体外活性：氟西汀可阻断海马细胞不可避免的休克 (IS) 引起的细胞增殖下调。氟西汀增加成年大鼠海马齿状回新生细胞的数量。氟西汀还可以增加前边缘皮质中增殖细胞的数量。氟西汀加速未成熟神经元的成熟。氟西汀增强齿状回神经发生依赖性长时程增强 (LTP)。氟西汀（但不是西酞普兰、氟伏沙明、帕罗西汀和舍曲林）会增加前额皮质中去甲肾上腺素和多巴胺的细胞外水平。急性全身给药后，氟西汀会导致去甲肾上腺素和多巴胺细胞外浓度的强劲和持续增加。细胞测定：在表达克隆的 5HT2C 受体或 5HT 受体的爪蟾细胞中，微摩尔浓度的氟西汀（百忧解）抑制血清素（5-羟色胺；5HT）引起的膜电流。对于 1 μM 5-HT 引起的反应，氟西汀的 IC50 约为 20 μM。 Fluoxetine 还抑制 [3H]5HT 与 HeLa 细胞中表达的 5HT2C 受体的结合，以及 [3H]5HT 与大鼠皮质膜中 5HT 受体的结合，Ki 分别为约 65–97 nM 和约 56 μM。服用氟西汀可阻断因不可避免的休克（IS）导致的海马细胞增殖的下调，从而导致行为绝望的状态。氟西汀增加了成年大鼠海马齿状回新生细胞的数量。氟西汀还增加了前边缘皮质中增殖细胞的数量。氟西汀加速未成熟神经元的成熟。氟西汀增强齿状回神经发生依赖性长时程增强（LTP）。氟西汀，而不是其他选择性血清素摄取抑制剂，如西酞普兰、氟伏沙明、帕罗西汀和舍曲林，可以增加前额皮质的去甲肾上腺素和多巴胺细胞外水平。急性全身给药后，氟西汀使细胞外去甲肾上腺素和多巴胺浓度强劲且持续增加。

氟西汀治疗还可以逆转成年雄性斯普拉格-道利大鼠暴露于不可避免的电击的动物中观察到的逃避潜伏期的缺陷。氟西汀与奥氮平联合使细胞外多巴胺 ([DA](ex)) 和去甲肾上腺素 ([NE](ex)) 水平强劲、持续增加，分别高达基线的 361% 和 272%，显着高于基线要么单独用药。

在表达克隆的 5HT2C 受体或 5HT 受体的爪蟾细胞中，微摩尔浓度的氟西汀 (Prozac) 抑制血清素（5-羟色胺；5HT）诱导的膜电流。对于 1 μM 5-HT 引起的反应，氟西汀的 IC50 约为 20 μM。此外，[3H]5HT 与大鼠皮质膜中 5HT 受体的结合以及 [3H]5HT 与 HeLa 细胞中表达的 5HT2C 受体的结合均被氟西汀抑制，Ki 值分别约为 65-97 nM 和 56 μM。氟西汀的使用可以防止不可避免的休克（IS）引起的海马细胞增殖下调，从而导致行为绝望的状态。在成年大鼠海马齿状回中，氟西汀增加了增殖细胞的数量。氟西汀也增加了前边缘皮层的增殖细胞计数。服用氟西汀时，中性粒细胞成熟得更快。氟西汀以神经发生依赖性方式增强齿状回的 LTP。在前额皮质中，氟西汀增加去甲肾上腺素和多巴胺细胞外水平，但不增加其他选择性血清素摄取抑制剂，如西酞普兰、氟伏沙明、帕罗西汀和舍曲林。急性全身给药后，氟西汀会显着且持久地增加多巴胺和去甲肾上腺素细胞外浓度。

Absorption, Distribution and Excretion
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
The average amount of drug in breastmilk is higher with fluoxetine than with most other SSRIs and the long-acting, active metabolite, norfluoxetine, is detectable in the serum of most breastfed infants during the first 2 months postpartum and in a few thereafter. Adverse effects such as colic, fussiness, and drowsiness have been reported in some breastfed infants. Decreased infant weight gain was found in one study, but not in others. No adverse effects on development have been found in a few infants followed for up to a year.
If fluoxetine is required by the mother, it is not a reason to discontinue breastfeeding. A safety scoring system finds fluoxetine use to be possible during breastfeeding, although others do not recommend its use. If the mother was taking fluoxetine during pregnancy or if other antidepressants have been ineffective, most experts recommend against changing medications during breastfeeding. Otherwise, agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. The breastfed infant should be monitored for behavioral side effects such as colic, agitation, irritability, poor feeding, and poor weight gain.
Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding, although this might be a reflection of their disease state. These mothers may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.
◉ Effects in Breastfed Infants
Colic, decreased sleep, vomiting and watery stools occurred in a 6-day-old breastfed infant probably caused by maternal fluoxetine. Two other reports of colic in breastfed infants, a 1.76-month-old and a 2-month-old, were possibly caused by fluoxetine in breastmilk. The older of the two also exhibited hyperactivity.
Another case of possible increased irritability in a 3-month-old was noted by a pediatrician observer, who was the infant’s father. However, the mother and the infant’s pediatrician disagreed.
Occurrence of hyperglycemia and glycosuria in a 5-month-old, possibly from fluoxetine in breastmilk was reported to the Australian Adverse Drug Reaction Advisory Committee.
A 3-day-old breastfed infant was difficult to arouse, ceased rooting behavior, decreased nursing, and was moaning and grunting. Although the infant had been exposed in utero and was somewhat drowsy during the first 2 days of life, symptoms became worse after the mother's milk came in on day 3. These effects were probably caused by fluoxetine in breastmilk.
Possible drug-induced seizure-like activity and cyanosis occurred in a breastfed 3-week-old breastfed infant whose mother was taking fluoxetine, carbamazepine and buspirone during pregnancy and breastfeeding.
One observational report of 4 infants found no apparent neurological abnormalities following exposure to fluoxetine in milk for 12 to 52 weeks.
A retrospective, case-control, cohort study compared the weights of the infants of mothers who took fluoxetine during pregnancy and breastfed for at least 2 weeks postpartum to the infants of mothers who took fluoxetine during pregnancy and did not breastfeed. Compared to controls, decreased weight gain occurred among the 26 infants exposed postpartum to fluoxetine in breastmilk, although the weights were still in the normal range.
A prospective study of 51 nursing women taking fluoxetine and 63 nursing women who took no fluoxetine found no effect on weight gain, but reported a greater frequency of unspecified side effects in the infants of mothers who took fluoxetine. This study's results have been reported only in abstract form, so some details are lacking.
In a prospective study of 40 women who took fluoxetine throughout pregnancy, 21 breastfed their infants (extent and duration not stated). Testing of the infants at 15 to 71 months of age found no differences in cognitive, language or temperament measurements between infants who were breastfed and those who were not.
In a study comparing the 31 infants of depressed mothers who took an SSRI during pregnancy for major depression with 13 infants of depressed mothers who did not take an SSRI, mental development and most motor development in both groups was normal at follow-up averaging 12.9 months. Three of the treated mothers took fluoxetine in doses averaging 23.3 mg daily for an average of 3 months while breastfeeding their infants. Psychomotor development was slightly delayed compared to controls, but the contribution of breastfeeding to abnormal development could not be determined.
Platelet serotonin levels were measured in 11 mothers and their breastfed infants after 4 to 12 weeks of fluoxetine therapy. Platelets and neurons both have the same serotonin transporter, so this effect on platelet serotonin might indicate potential effects on the nervous system of some breastfed infants. Maternal fluoxetine dosages ranged from 20 to 40 mg daily. Ten of the infants were under 6 months of age and 4 were under 3 months of age at the start of therapy; 6 were exclusively breastfed. Although maternal platelet serotonin levels were decreased from 157 mcg/L to 23 mcg/L by fluoxetine therapy, average infant serotonin levels were 217 mcg/L before and 230 mcg/L after maternal therapy. These findings indicate that the amount of fluoxetine ingested by the infants was not sufficient to affect serotonin transport in platelets in most breastfed infants. However, 3 infants experienced drops in platelet serotonin of 13, 24 and 60%, respectively. The latter infant was the only one with measurable fluoxetine plasma levels as well as norfluoxetine, but the infant had no discernible adverse effects. One other infant had a delay in motor development at 24 weeks, but had normal mental development; 6 other infants were within 1 standard deviation of normal in both measures when tested between 24 and 56 weeks of age.
Twenty-nine mothers who took fluoxetine in an average dosage of 34.6 mg daily for depression or anxiety starting no later than 4 weeks postpartum, breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and mothers reported no abnormal effects in their infants.
One study of side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluoxetine. No specific information on maternal fluoxetine dosage, extent of breastfeeding or infant age was reported.
Eleven infants who were breastfed (extent and duration not stated) during maternal use of fluoxetine for depression (n = 5) or panic disorder (n = 6) had normal weight gain at 12 months of age that was not significantly different from a control group of infants whose mothers took no psychotropic medications. Neurologic development was also normal at 12 months of age.
In 1 breastfed (extent not stated) infant aged 11 weeks whose mother was taking fluoxetine 20 mg daily, no adverse reactions were noted clinically at the time of the study.
A small study compared the reaction to pain in infants of depressed mothers who had taken an SSRI during pregnancy alone or during pregnancy and nursing to a control group of unexposed infants of nondepressed mothers. Infants exposed to an SSRI either prenatally alone or prenatally and postnatally via breastmilk had blunted responses to pain compared to control infants. Seven of the 30 infants were exposed to fluoxetine. Because there was no control group of depressed, nonmedicated mothers, an effect due to maternal behavior caused by depression could not be ruled out. The authors stressed that these findings did not warrant avoiding drug treatment of depression during pregnancy or avoiding breastfeeding during SSRI treatment.
An infant was born to a mother taking fluoxetine 40 mg daily, oxycodone 20 mg 3 times daily, and quetiapine 400 mg daily. The infant was breastfed 6 to 7 times daily and was receiving 120 mcg of oral morphine 3 times daily for opiate withdrawal. Upon examination at 3 months of age, the infant's weight was at the 25th percentile for age, having been at the 50th percentile at birth. The authors attributed the weight loss to opiate withdrawal. The infant's Denver developmental score was equal to his chronological age.
An uncontrolled online survey compiled data on 930 mothers who nursed their infants while taking an antidepressant. Infant drug discontinuation symptoms (e.g., irritability, low body temperature, uncontrollable crying, eating and sleeping disorders) were reported in about 10% of infants. Mothers who took antidepressants only during breastfeeding were much less likely to notice symptoms of drug discontinuation in their infants than those who took the drug in pregnancy and lactation.
A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Fifteen of the infants were exposed to fluoxetine in utero.
A late preterm infant was born to a mother who took fluoxetine 60 mg daily throughout pregnancy and during exclusive breastfeeding. At 7 days of age, the infant was found to be having jerking movements, with hypertonia and hyperreflexia as well as tachypnea and compensated metabolic acidosis. The infant's Finnegan scores were the range of 7 to 10. On day 8 of life, the infant had a serum fluoxetine level of 120 mcg/L, which is similar to therapeutic adult levels. Breastfeeding was discontinued and after 5 days of formula feeding the infant's Finnegan scores had decreased to a range of 3 to 6. After 10 days of formula, most symptoms had subsided. At 3 months of age, the infant was growing and developing normally. The infant's symptoms were attributed to serotonin syndrome caused by the high levels of fluoxetine rather than to withdrawal. The reaction was probably caused by fluoxetine and breastfeeding might have contributed to maintaining the high fluoxetine levels after birth.
A woman with narcolepsy took sodium oxybate 4 grams each night at 10 pm and 2 am as well as fluoxetine 20 mg and cetirizine 5 mg daily throughout pregnancy and postpartum. She breastfed her infant except for 4 hours after the 10 pm oxybate dose and 4 hours after the 2 am dose. She either pumped breastmilk or breastfed her infant just before each dose of oxybate. The infant was exclusively breastfed or breastmilk fed for 6 months when solids were introduced. The infant was evaluated at 2, 4 and 6 months with the Ages and Stages Questionnaires, which were withing the normal range as were the infant's growth and pediatrician's clinical impressions regarding the infant's growth and development.
Two women were treated with fluoxetine 20 mg daily during the third trimester of pregnancy and during breastfeeding. Pediatric evaluations including neurologic assessments and brain ultrasound were conducted during the first 24 hours postpartum. Further follow-up was conducted at 6 or more months of age. Infant clinical status was comparable to unexposed infants from the same pediatric department.
A woman was taking fluoxetine 40 mg daily during pregnancy and postpartum for depression. She breastfed (extent not stated) her infant. A venous cord gas taken at delivery showed a pH of 7.38. At 45 minutes postpartum, the baby developed respiratory distress syndrome with mixed respiratory and metabolic acidosis, becoming cyanosed and floppy requiring admission to the neonatal unit. Glucose was 3.4 mmol/L on admission. Abnormal movements, tremor, and extensor posturing were present initially, but resolved within hours, although irritability and poor sleep were noted subsequently. The mother discontinued breastfeeding and the infant’s symptoms improved, although the infant had low levels of fluoxetine and norfluoxetine in his blood. The infant was discharged at age 16 days of age. The authors attributed the infant’s symptoms to a serotonin syndrome caused by fluoxetine.
◉ Effects on Lactation and Breastmilk
Fluoxetine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients. Euprolactinemic galactorrhea has also been reported. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluoxetine was found to have a 3.6-fold increased risk of causing hyperprolactinemia compared to other drugs. Preliminary animal and in vitro studies found that fluoxetine may have some estrogenic activity. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior compared to the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.
A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; fluoxetine n = 21) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

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N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) is a hydrochloride and a N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine.
Fluoxetine Hydrochloride is the hydrochloride salt form of fluoxetine, a diphenhydramine derivative and selective serotonin reuptake inhibitor with antidepressant, anti-anxiety, antiobsessional and antibulimic activity and with potential immunomodulating activity. Upon administration, fluoxetine binds to the presynaptic serotonin (5-HT) receptor resulting in negative allosteric modulation of the receptor complex, thereby blocking recycling of serotonin by the presynaptic receptor. Inhibition of serotonin reuptake by fluoxetine enhances serotonergic function through serotonin accumulation in the synaptic space, resulting in long-term desensitization and downregulation of 5-HT receptors, preventing 5-HT-mediated signaling and leading to antidepressant, anti-anxiety, antiobsessional and antibulimic effects. In addition, fluoxetine may inhibit the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6). This may prevent IL-6-mediated inflammation and cytokine storm.
The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants.
See also: Fluoxetine (has active moiety); Fluoxetine Hydrochloride; Olanzapine (component of).

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Mechanism of Action
The precise mechanism of antidepressant action of fluoxetine is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. Fluoxetine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.
Monoamine oxidase-B has been determined to be the enzyme responsible for the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into its toxic metabolite 1-methyl-4-phenylpyridine ion. Since this enzyme has been localized primarily in astrocytes and serotonergic neurons, it would appear that 1-methyl-4-phenylpyridine ion is being produced outside the dopaminergic neurons. To investigate this possibility, the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was preceded by systemically administered fluoxetine. In keeping with its demonstrated ability to inhibit uptake into serotonergic neurons and serotonin uptake into astrocytes, fluoxetine pretreatment resulted in a significant attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced depletions of striatal dopamine and serotonin concentration. These results support the extra-dopaminergic production of 1-methyl-4-phenylpyridine ion.
Fluoxetine is a potent and selective inhibitor of the neuronal serotonin-uptake carrier and is a clinically effective antidepressant. Although fluoxetine is used therapeutically as the racemate, there appears to be a small but demonstrable stereospecificity associated with its interactions with the serotonin-uptake carrier. The goals of this study were to determine the absolute configurations of the enantiomers of fluoxetine and to examine whether the actions of fluoxetine in behavioral tests were enantiospecific. (S)-Fluoxetine was synthesized from (S)-(-)-3-chloro-1-phenylpropanol by sequential reaction with sodium iodide, methylamine, sodium hydride, and 4-fluorobenzotrifluoride. (S)-Fluoxetine is dextrorotatory (+1.60) in methanol, but is levorotatory (-10.85) in water. Fluoxetine enantiomers were derivatized with (R)-1-(1-naphthyl)ethyl isocyanate, and the resulting ureas were assayed by 1H NMR or HPLC to determine optical purities of the fluoxetine samples. Both enantiomers antagonized writhing in mice; following sc administration of (R)- and (S)-fluoxetine, ED50 values were 15.3 and 25.7 mg/kg, respectively. Moreover, both enantiomers potentiated a subthreshold analgesic dose (0.25 mg/kg) of morphine, and ED50 values were 3.6 and 5.7 mg/kg, respectively. Following ip administration to mice, the two stereoisomers antagonized p-chloroamphetamine-induced depletion of whole brain serotonin concentrations. ED50 values for (S)- and (R)-fluoxetine were 1.2 and 2.1 mg/kg, respectively. The two enantiomers decreased palatability-induced ingestion following ip administration to rats; (R)- and (S)-fluoxetine reduced saccharin-induced drinking with ED50 values of 6.1 and 4.9 mg/kg, respectively. Thus, in all biochemical and pharmacological studies to date, the eudismic ratio for the fluoxetine enantiomers is near unity.

C17H19CLF3NO

345.79

345.11

C, 59.05; H, 5.54; Cl, 10.25; F, 16.48; N, 4.05; O, 4.63

56296-78-7

Fluoxetine; 54910-89-3; (S)-Fluoxetine hydrochloride; 114247-06-2; (R)-Fluoxetine hydrochloride; 114247-09-5

62857

White to off-white solid powder

395.1ºC at 760mmHg

158-159°C

192.8ºC

5.627

21.26

2

5

6

23

308

0

Cl[H].FC(C1C([H])=C([H])C(=C([H])C=1[H])OC([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])C([H])([H])N([H])C([H])([H])[H])(F)F

GIYXAJPCNFJEHY-UHFFFAOYSA-N

InChI=1S/C17H18F3NO.ClH/c1-21-12-11-16(13-5-3-2-4-6-13)22-15-9-7-14(8-10-15)17(18,19)20;/h2-10,16,21H,11-12H2,1H3;1H

N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine;hydrochloride

2922.39.4500

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.23 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.23 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.23 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 13 mg/mL (37.60 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。