In a mouse model of IHKA, macimorelin (5 mg/kg, intraperitoneally, twice daily for 2 weeks) decreases the frequency and length of seizures [2].

Animal/Disease Models: Intrahippocampal kainic acid (IHKA) mouse model [2]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection twice a day for two weeks.
Experimental Results: The number and duration of seizures were Dramatically diminished during treatment, but there was no anti-epileptogenic or disease-modifying effect.

Absorption, Distribution and Excretion
Macimorelin is a novel, synthetic ghrelin agonist, which is readily absorbed from the gastrointestinal tract. The maximum plasma concentration (Cmax) was observed between 0.5 and 1.5 hours following oral administration of 0.5mg/kg macimorelin to patients with AGHD under fasting for at least 8 hours. Higher doses of drug demonstrate a dose-proportional increase in plasma concentrations. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, respectively.
Following a single oral dose of 0.5 mg/kg macimorelin, the mean volume of distribution of the central compartment is 5,733.4 ± 565.7L.
Following a single oral dose of 0.5 mg/kg macimorelin, the mean clearance over the fraction absorbed (Cl/F) was 37,411.0 ± 4,554.6 mL/min.

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Metabolism / Metabolites
Macimorelin predominantly undergoes CYP3A4-mediated metabolism according to an *in vitro* human liver microsomes study.

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Biological Half-Life
The mean terminal half-life (T1/2) is 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects.

[1]. Macimorelin as a Diagnostic Test for Adult GH Deficiency. J Clin Endocrinol Metab. 2018 Aug 1;103(8):3083-3093.

[2]. Translational potential of the ghrelin receptor agonist macimorelin for seizure suppression in pharmacoresistant epilepsy. Eur J Neurol. 2021 Sep;28(9):3100-3112.

[3]. Ali SA, Garcia JM. Randomized clinical trial of the novel oral ghrelin mimetic macimorelin in the treatment of cancer cachexia: study design and preliminary results. Endocr Rev. 2013;34:.

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer. Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability. Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.
Macimorelin is a Growth Hormone Secretagogue Receptor Agonist. The mechanism of action of macimorelin is as a Growth Hormone Secretagogue Receptor Agonist.
Macimorelin is an orally available synthetic mimetic of the growth hormone (GH) secretagogue ghrelin with potential anti-cachexia activity. Upon oral administration, macimorelin mimics endogenous ghrelin by stimulating appetite and binds to the growth hormone secretagogue receptor GHSR in the central nervous system, thereby mimicking the GH-releasing effects of ghrelin from the pituitary gland. Stimulation of GH secretion increases insulin-like growth factor-I (IGF-I) levels which may further stimulate protein synthesis. In addition, ghrelin reduces the production of pro-inflammatory cytokines, which may play a direct role in cancer-related loss of appetite.
See also: Macimorelin Acetate (is active moiety of).

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Drug Indication
Indicated for the diagnosis of adult growth hormone deficiency (AGHD).
FDA Label
This medicinal product is for diagnostic use only.  GHRYVELIN is indicated for the diagnosis of growth hormone deficiency (GHD) in adults.
Diagnosis of growth hormone deficiency

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Mechanism of Action
Ghrelin is an endogenous ligand for the GH secretagogue receptor that is also called the ghrelin receptor (GHS-R1a). Upon activation of the receptor, ghrelin serves to increase growth hormone (GH) secretion. Macimorelin mimics the actions of ghrelin by stimulating GH release. As a synthetic agonist, it activates growth hormone secretagogue receptors present in the pituitary and hypothalamus.

C26H30N6O3

474.55

474.237

381231-18-1

Macimorelin acetate;945212-59-9

9804938

Typically exists as solid at room temperature

1.3±0.1 g/cm3

948.6±65.0 °C at 760 mmHg

527.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.676

2.64

6

4

9

35

761

2

CC(C(N[C@@H](C(N[C@@H](NC=O)CC1=CNC2=CC=CC=C12)=O)CC3=CNC4=CC=CC=C34)=O)(N)C

UJVDJAPJQWZRFR-DHIUTWEWSA-N

InChI=1S/C26H30N6O3/c1-26(2,27)25(35)31-22(11-16-13-28-20-9-5-3-7-18(16)20)24(34)32-23(30-15-33)12-17-14-29-21-10-6-4-8-19(17)21/h3-10,13-15,22-23,28-29H,11-12,27H2,1-2H3,(H,30,33)(H,31,35)(H,32,34)/t22-,23-/m1/s1

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)

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.)