After oxidative breakdown, flibanserin (0.01-100 μM; 72 h) can be broken down into two potentially non-toxic degradation products, DP1 and DP2 [1]. Determination of cell viability [1]

In the hippocampus, midbrain, and prefrontal cortex, flibanserin (1, 10, 30 mg/kg; i.p.; single dosage) has unique pharmacological characteristics. The cortex may be more responsive than other brain regions because 5-HT1A receptors are found there [2]. The mesolimbic dopaminergic system and the hypothalamic structures involved in integrating sexual cues associated to sexual motivation are preferentially activated by flibanserin (15, 45 mg/kg; oral; twice daily; 22 days)[3]. Flibanserin (5, 10, 25, and 50 mg/kg; subcutaneous injection; single dosage) reduces anxiety without causing adverse motor effects in a rat ultrasonic vocalization paradigm [4].

Cell viability determination [1]
Cell Types: NHSF cell lin
Tested Concentrations: 0.01, 0.1, 1, 10, 100 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Cell viability reached 97.91% (DP1) and 96.73% (DP2) at 0.01 μM. Non-toxic at concentrations up to 100 μM (IC50 >100 μM).

Animal/Disease Models: Long Evans female rat (225-250 g) [3]
Doses: 15 mg/kg; 45 mg/kg
Route of Administration: po (oral gavage); twice (two times) daily for 22 days
Experimental Results: Ventral tegmental area The density of activated catecholaminergic neurons increased, but not in the locus coeruleus. After long-term 22-day treatment, Fos expression increased in the medial preoptic area and arcuate nucleus of the hypothalamus, ventral tegmental area, locus coeruleus, and lateral paragigantocellular nucleus.

---

Animal/Disease Models: Infant rat anxiety ultrasonic vocalization model [4]
Doses: 5, 10, 25 and 50 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: Ultrasonic vocalization of infant mice diminished. Shown to be effective within 30 minutes, with no serious motor side effects at active doses.

---

Male Sprague-Dawley rats (250–350 g) were used. Rats were anesthetized with Equithesin (3.5 mL/kg) and implanted with concentric microdialysis probes in the prefrontal cortex, ventral hippocampus, or dorsal raphe nucleus. Probes were perfused with artificial cerebrospinal fluid (aCSF) containing 1 μM citalopram at 1 μL/min. After 24 h recovery, 30-min dialysate samples were collected. Following stabilization of basal monoamine levels, rats received intraperitoneal injections of flibanserin (3 or 10 mg/kg) or vehicle. Flibanserin was dissolved in a vehicle containing 250 mL/L polyethylene glycol-400 and 22.7 mL/L 1 M HCl, warmed to approximately 40°C. In antagonist experiments, WAY100,635 (0.3 mg/kg) was injected subcutaneously 30 min before flibanserin. Dialysate samples were analyzed by HPLC with electrochemical detection for 5-HT, DA, and NA [2].

Absorption, Distribution and Excretion
The absolute oral bioavailability of flubancerin is 33%. Following a single oral dose of 50 mg flubancerin solution, the drug is primarily excreted via feces (51%) and urine (44%). Approximately 98% of the drug binds to human serum proteins, primarily albumin. Food can increase the extent of absorption of 50 mg flubancerin (half the recommended dose) and slow its absorption rate. Low-fat, medium-fat, and high-fat diets increased the AUC0-inf of flubancerin by 1.18-fold, 1.43-fold, and 1.56-fold, respectively; Cmax increased by 1.02-fold, 1.13-fold, and 1.15-fold, respectively; and, in the fasting state, the median time to peak concentration (Tmax) increased from 0.8 hours to 1.5 hours, 0.9 hours, and 1.8 hours, respectively.
In healthy premenopausal women (N=8), after a single oral dose of 100 mg flubancerin, the mean (standard deviation) Cmax was 419 (206) ng/mL, and the mean (standard deviation) AUC0-inf was 1543 (511) nghr/mL. The median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. The absolute bioavailability of flubancerin after oral administration was 33%.
/Milk/ Flubancerin is secreted into rat milk. It is currently unknown whether flubancerin is present in human milk…

---

Metabolism/Metabolites
Flubancerin is primarily metabolized via CYP3A4, with a small amount metabolized via CYP2C19. The involvement of CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 is minimal. Flubancelin produces at least 35 metabolites, two of which reach plasma concentrations comparable to the parent drug, but these are pharmacologically inactive. Flubancelin is primarily metabolized via CYP3A4, with lower levels of metabolism via CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of flubancelin. Following a single oral administration of 50 mg of 14C-labeled flubancelin solution, 44% of the 14C-labeled flubancelin-related radioactive material was recovered in urine and 51% in feces. Flubancelin is extensively metabolized into at least 35 metabolites, most of which are present at low plasma concentrations. Two metabolites have plasma concentrations similar to those of flubancelin: 6,21-dihydroxy-flubancelin-6,21-disulfate and 6-hydroxy-flubancelin-6-sulfate. These two metabolites are inactive.

---

Biological half-life
≈11 hours
The average terminal half-life of fluorobenzamine is approximately 11 hours.

Toxicity Summary
Identification and Uses: Flubancelin (brand name Addyi) is a non-hormonal drug approved for the treatment of systemic hyposexuality (HSDD) in premenopausal and postmenopausal women. Human Exposure and Toxicity: The adverse reaction spectrum of flubancelin is similar to that of other centrally acting drugs. In human exposure studies, the most common reported adverse reaction was sedation/drowsiness. Dizziness, nausea, fatigue, and drowsiness have also been reported. Flubancelin can cause central nervous system depression. Use of flubancelin in patients with impaired hepatic function can increase flubancelin blood concentrations, leading to severe hypotension and syncope. Patients taking intermediate to potent CYP3A4 inhibitors also have an increased risk of hypotension and syncope. Alcohol consumption also increases the risk of severe hypotension and syncope in patients taking flubancelin. Flubancelin has preferential affinity for serotonin 5-HT (1A), dopamine D (4kA), and serotonin 5-HT (2A) receptors. In vitro and microelectrophoresis experiments have shown that flubancelin can act as a 5-HT(1A) receptor agonist, a weak partial agonist of dopamine D(4) receptors, and a 5-HT(2A) receptor antagonist. Flubancelin has not shown consistent efficacy in animal models of anxiety and appears to have potential antipsychotic effects. Flubancelin may cause some sedation, but no significant toxicity has been observed at pharmacologically relevant doses. Animal studies: Mammary tumors were observed in female mice in carcinogenicity studies. Hepatocellular carcinoma has been reported in both female and male mice, but these effects were only observed in animals treated with 3–10 times the clinically recommended dose of flubancelin.

---

Hepatotoxicity
In placebo-controlled trials, the incidence of liver dysfunction was not higher in the flubancelin group than in the placebo group, and the abnormalities were mild and resolved spontaneously, usually without the need for discontinuation of treatment. No cases of acute liver injury with jaundice caused by flubancelin have been reported during these premarketing clinical trials and after the wider use of flubancelin. However, clinical experience with flubancerine is generally limited. Many other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), have been associated with rare cases of clinically significant liver injury. The latency period for liver injury is typically 1 to 8 weeks, with varying patterns of enzyme elevation, ranging from cholestatic to hepatocellular. Mild signs and symptoms of hypersensitivity (rash, fever, eosinophilia) are common but usually not pronounced. Autoantibody formation is rare. The course is usually self-limiting, with mild to moderate severity, although some SSRIs have been reported to cause death. However, flubancerine itself has not been associated with similar cases. Probability score: E (Unproven but suspected cause of clinically significant liver injury). Protein binding rate: Approximately 98%, highly bound to serum proteins (primarily albumin).

---

Drug Interactions
Addyi, when used in combination with digoxin (a drug transported by P-glycoprotein (P-gp)), increases digoxin concentration. This may lead to digoxin toxicity.
This study investigated the functional interactions of the antidepressants amitriptyline, mianserin, maprotiline, imipramine, fluoxetine, and the potential antidepressant flubancerin on the 5-HT7 receptor-mediated serotonin (5-CT) response in the guinea pig ileum. 5-CT can inhibit the contractile response induced by substance P (100 nM) in a concentration-dependent manner. Except for fluoxetine and flubancerin, all antidepressants antagonized the inhibitory effect of 5-CT to varying degrees, with the affinity order being: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to exhibit competitive antagonism against the 5-HT7 receptor within a tenfold concentration range (0.1–1 μM), with an affinity (pA2) value of 8.1 ± 0.6. The antagonistic effects of other antidepressants were not concentration-dependent (amitriptyline) or associated with a slight to moderate reduction in the maximum 5-CT response (imipramine or maprotiline). Apparent affinity (pKB) values were: amitriptyline, 7.0 ± 0.2; maprotiline, 7.3 ± 0.6; imipramine, 7.2 ± 0.4. Our results indicate that multiple antidepressants from different chemical classes can antagonize the gut 5-HT7 receptor through competitive or allosteric mechanisms. This evidence expands upon our previous findings, confirming the interactions of antidepressants with other 5-HT receptors (i.e., 5-HT3 and 5-HT4 receptors).
Compared to Addyi alone, Addyi co-administered with CYP3A4 inducers significantly reduces flubancelin exposure. Examples of CYP3A4 inducers include carbamazepine, phenobarbital, phenytoin sodium, rifabutin, rifampin, rifapastatin, and St. John's wort.
Addyi co-administered with potent CYP2C19 inhibitors may increase flubancelin exposure, thereby increasing the risk of hypotension, syncope, and central nervous system depression. Examples of potent CYP2C19 inhibitors include proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals.
For more complete data on interactions with flubancelin (10 in total), please visit the HSDB record page.

[1]. Insights into Flibanserin Oxidative Stress Degradation Pathway: In Silico – In Vitro Toxicity Assessment of Its Degradates. New Journal of Chemistry, 2021.

[2]. A potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors. Br J Pharmacol. 2003 Aug;139(7):1281-8.

[3]. Brain neuronal activation induced by flibanserin treatment in female rats. Psychopharmacology (Berl). 2013 Dec;230(4):639-52.

[4]. Flibanserin has anxiolytic effects without locomotor side effects in the infant rat ultrasonic vocalization model of anxiety. Br J Pharmacol. 2000 Jun;130(4):739-46.

[5]. Flibanserin for hypoactive sexual desire disorder: place in therapy. Ther Adv Chronic Dis. 2017 Jan;8(1):16-25.

Therapeutic Uses
ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Flubaneseline is included in the database. Addyi is indicated for the treatment of acquired, generalized hyposexuality disorder (HSDD) in premenopausal women, characterized by low libido that causes significant distress or difficulty in interpersonal relationships and is not caused by comorbid medical or psychiatric illness, partner problems, or the effects of medications or other drug substances. Acquired HSDD refers to HSDD occurring in patients who did not previously have sexual desire problems. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulus, situation, or partner. /US product label includes/
A core issue in the treatment of Parkinson's disease (PD) is the development of motor disorders, such as levodopa-induced motor disorder (LID), following long-term treatment. Preclinical and clinical studies have shown that serotonin (5-HT(1A)) receptor agonists can alleviate this disabling motor side effect. This study aimed to investigate whether flubancelin, compared to buspirone, could alleviate contralateral circling behavior sensitized by levodopa in hemilateral Parkinson's disease rats (an animal model of levodopa-induced motor disorder). Both drugs have preferential affinity for the 5-HT(1A) receptor of serotonin. Buspirone was chosen as a control because it was expected to have an effect in this model. Rats with unilateral 6-hydroxydopamine injury were intraperitoneally injected twice daily with levodopa methyl ester (12.5 mg/kg) and benserazide (3.25 mg/kg) for 21 days (administered on days 1, 3, 5, 8, 11, 14, 17, and 21, respectively). On day 24, L-DOPA-sensitized rats were intraperitoneally injected with saline (control group), 2.5, 5, and 10 mg/kg of buspirone, or flubancerine, respectively, 5 minutes before administration of L-DOPA methyl ester and benserazide. Acute administration of flubancerine and buspirone dose-dependently attenuated the increase in contralateral circling behavior. At doses of 5 mg/kg buspirone and 10 mg/kg flubancerine, the circling response was almost completely inhibited. Current preclinical results further suggest that the 5-HT(1A) receptor is a promising therapeutic target for reducing levodopa-induced dyskinesia (LID) and predict potential efficacy of flubancelin in treating LID associated with Parkinson's disease (PD).

---

Drug Warnings
/Box Warning/ Addyi may increase flubancelin concentrations in patients with impaired liver function, potentially leading to severe hypotension and syncope. Therefore, Addyi is contraindicated in patients with impaired liver function. CYP3A4 inhibitors are contraindicated in patients taking Addyi.
/Black Box Warning/ Concomitant use of Addyi with intermediate or strong CYP3A4 inhibitors may increase flubancelin blood concentrations, potentially leading to severe hypotension and syncope. Therefore, intermediate or strong CYP3A4 inhibitors are contraindicated in patients taking Addyi.
/Black Box Warning/ Concomitant use of Addyi with alcohol may increase the risk of severe hypotension and syncope. Therefore, alcohol is contraindicated in patients taking Addyi. Before prescribing Addyi, the patient's likelihood of abstaining from alcohol should be assessed, taking into account their current drinking habits, past drinking history, and other relevant social and medical history. Patients taking Addyi should be informed of the importance of abstaining from alcohol. Because interactions with alcohol increase the risk of hypotension and syncope, Addyi should only be obtained through a restrictive program under a risk assessment and mitigation strategy (REMS) program called the Addyi REMS program. Addyi can cause central nervous system depression (e.g., drowsiness, sedation). In five 24-week randomized, placebo-controlled, double-blind trials in premenopausal women with hyposexuality disorder (HSDD), the incidence of drowsiness, sedation, or fatigue was 21% in the group taking 100 mg Addyi daily at bedtime, compared to 8% in the placebo group. The risk of central nervous system depression increases if Addyi is taken while awake, or concomitantly with alcohol or other central nervous system depressants, or with medications that can increase flubanxerin concentrations (e.g., CYP3A4 inhibitors). For more complete data on drug warnings for flubancerline (9 in total), please visit the HSDB records page.

C20H21F3N4O

390.41

390.167

167933-07-5

Flibanserin-d4-1;2122830-91-3;Flibanserin hydrochloride;147359-76-0;Flibanserin-d4;2122830-90-2

6918248

White to off-white solid powder

1.292 g/cm3

1.566

3.173

1

6

4

28

550

0

FC(C1C([H])=C([H])C([H])=C(C=1[H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])N2C(N([H])C3=C([H])C([H])=C([H])C([H])=C23)=O)C([H])([H])C1([H])[H])(F)F

PPRRDFIXUUSXRA-UHFFFAOYSA-N

InChI=1S/C20H21F3N4O/c21-20(22,23)15-4-3-5-16(14-15)26-11-8-25(9-12-26)10-13-27-18-7-2-1-6-17(18)24-19(27)28/h1-7,14H,8-13H2,(H,24,28)

3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1H-benzimidazol-2-one

BIMT 17; BIMT 17BS; EBD 6396; BIMT17; BIMT17BS; EBD-6396; BIMT-17; BIMT-17BS; EBD6396; Flibanserin. trade name: Addyi;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~50 mg/mL (~128.07 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)