In female stents treated with estradiol, benzoate, and progesterone, gepirone (0–3 mg/kg, i.p.) responds to progesterone at the 5-HT1A receptor and decreases lordotic behavior [1]. In addition, gepirone (10–15 mg/kg, subcutaneous injection, 2, 7, 14 days) activates the Sprague-Dawley morphology of postsynaptic, normally sensitive 5-HT1A receptors [2].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat [2]
Doses: 10, 15 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: The number and firing rate of spontaneously active 5-HT neurons were diminished. Unmodified by long-term treatment, the ED50 value was 10.1 ± 0.5 μg/kg in control rats and 9.7 ± 1.9 μg/kg in treated rats.

Absorption, Distribution and Excretion
The pharmacokinetics of gepirone are linear and dose-proportional from 18.2 mg to 72.6 mg. Steady-state plasma concentrations are typically achieved within two to four days of daily dosing. The absolute bioavailability is 14% to 17%. The maximal plasma gepirone concentration (Cmax) after dosing is reached within 6 hours post-dose (Tmax). After a high-fat meal, Tmax is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (Cmax) of gepirone and, to a lesser extent, on the total exposure (AUC0-tlast, AUC0-∞) to gepirone. The magnitude of the food effect was dependent of the fat content of the meal. The systemic exposure of gepirone and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone Cmax after intake of a low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher, and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state. The AUC after intake of a low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher, and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on Cmax and AUC of the major metabolites 3-OH-gepirone and 1PP were similar to that found for gepirone.
Following a single oral dose of [¹⁴C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of gepirone.
The apparent volume of distribution of gepirone is approximately 94.5L.
After the administration of 80 mg of gepirone, the apparent clearance of gepirone and its 2 metabolites, 1-PP and 3’-OH-gepirone, was calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h respectively.

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Metabolism / Metabolites
Gepirone is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites.
Gepirone has known human metabolites that include 2-(1-piperazinyl)pyrimidine, 3-Hydroxy-1-[4-[4-(5-hydroxypyrimidin-2-yl)piperazin-1-yl]butyl]-4,4-dimethylpiperidine-2,6-dione, 1-[4-[4-(5-Hydroxypyrimidin-2-yl)piperazin-1-yl]butyl]-4,4-dimethylpiperidine-2,6-dione, and 3-Hydroxygepirone.

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Biological Half-Life
The mean terminal half-life is approximately 5 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of gepirone during breastfeeding. The drug has poor oral bioavailability, so the infant is unlikely to absorb large amounts. Monitor breastfed infants for adverse reactions, such as irritability, restlessness, excessive somnolence, decreased feeding, and weight loss. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
The in vitro plasma protein binding in humans is 72% and is not concentration-dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP.

[1]. Effects of 5-HT1A selective anxiolytics on lordosis behavior: interactions with progesterone. Eur J Pharmacol. 1986 Dec 16;132(2-3):323-6.

[2]. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse. 1987;1(5):470-80.

Gepirone is a member of the class of piperidones that is piperidine-2,6-dione substituted by a 4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl group at position 1 and two methyl groups at position 4. It has a role as a serotonergic agonist, an antidepressant and an anxiolytic drug. It is a member of pyrimidines, a N-alkylpiperazine and a member of piperidones. It is a conjugate base of a gepirone(1+).
Gepirone, an azapirone, is a pharmacologic analog of [buspirone] that acts selectively on the pre- and post-synaptic 5HT1A receptors. Although earlier clinical trials showed promising results for gepirone, its formulation as an immediate-release tablet necessitates frequent administration due to the short half-lives. It was not until an extended-release formulation of gepirone was made available that gepirone became a potential candidate for a new antidepressant. Gepirone was approved by the FDA on September 28, 2023, under the brand name EXXUA for the treatment of adults with major depressive disorder. It represents a novel class of antidepressants that selectively targets the 5HT1A receptors, thus possessing a more favorable side effects profile with comparable incidence of sexual dysfunction side effects as that of the placebo.

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Drug Indication
Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults.

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Mechanism of Action
The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT_1a receptors. Particularly, gepirone

C19H29N5O2

359.474

359.232

83928-76-1

Gepirone-d8;2749331-28-8

55191

Off-white to light yellow solid powder

1.1±0.1 g/cm3

562.3±60.0 °C at 760 mmHg

293.8±32.9 °C

0.0±1.5 mmHg at 25°C

1.542

2.95

0

6

6

26

476

0

QOIGKGMMAGJZNZ-UHFFFAOYSA-N

InChI=1S/C19H29N5O2/c1-19(2)14-16(25)24(17(26)15-19)9-4-3-8-22-10-12-23(13-11-22)18-20-6-5-7-21-18/h5-7H,3-4,8-15H2,1-2H3

4,4-Dimethyl-1-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]piperidine-2,6-dionehydrochloride

MJ-13805B; MY-13805; Gepirone hydrochloride, Gepirone HCl; Exxua

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ~33.33 mg/mL (~92.72 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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