In the MCF7/ADR cell line, megestrol acetate alone causes an ICKY of 48.7 p,M[2].

Megestrol acetate can lessen the weight loss brought on by the MAC16 tumor and TNF when administered subcutaneously daily for seven days at a dose of 100 or 300 mg/kg[1].

Animal/Disease Models: Pure strain female NMRI mice (age 6 to 8 weeks)[1].
Doses: 100 or 300 mg/kg (50 mg megestrol acetate was suspended in 3 ml of pure corn oil).
Route of Administration: subcutaneously (sc) daily over a 7-day period.
Experimental Results: Produced a highly significant reversal of the TNF-induced decrease in body weight, accompanied by a significant increase in both food and water intake. Caused an increase in body weight over a 24-hour period to female NMRI mice. No effect on blood glucose levels in saline controls, concurrent Administration of megestrol acetate with TNF caused a significant increase in blood glucose compared with administration of TNF alone. Caused a dose-related reduction in the loss of host body weight in animals bearing the MAC16 tumour.

Absorption, Distribution and Excretion
Variable, but well absorbed orally.
The major route of drug elimination in humans is urine. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.

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Metabolism / Metabolites
Primarily hepatic. Megestrol metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces. No active metabolites have been identified.

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Biological Half-Life
34 hours

[1]. Effect of megestrol acetate on weight loss induced by tumour necrosis factor alpha and a cachexia-inducing tumour (MAC16) in NMRI mice. Br J Cancer. 1990 Sep;62(3):420-4.

[2]. Sensitization to doxorubicin resistance in breast cancer cell lines by tamoxifen and megestrol acetate. Biochem Pharmacol. 1996 Oct 11;52(7):1097-102.

[3]. Acute therapy with megestrol acetate decreases nuclear and cytosol androgen receptors in human BPH tissue. Prostate. 1982;3(1):11-5.

[4]. Megestrol acetate for treatment of cachexia associated with human immunodeficiency virus (HIV) infection. Ann Intern Med. 1988 Nov 15;109(10):840-1.

[5]. Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation. J Cachexia Sarcopenia Muscle. 2016 Dec;7(5):555-566.

Megestrol Acetate can cause cancer and developmental toxicity according to state or federal government labeling requirements.
Megestrol acetate is a steroid ester resulting from the formal condensation of the hydroxy group of megestrol with the carboxy group of acetic acid. It is an appetite stimulant used for the treatment of anorexia and cachexia. Also used for birth control and for the treatment of breast cancer. It has a role as an antineoplastic agent, an appetite enhancer, a contraceptive drug, a progestin and a synthetic oral contraceptive. It is a steroid ester, an acetate ester, a 20-oxo steroid and a 3-oxo-Delta(4) steroid. It is functionally related to a megestrol.
17-Hydroxy-6-methylpregna-3,6-diene-3,20-dione. A progestational hormone used most commonly as the acetate ester. As the acetate, it is more potent than progesterone both as a progestagen and as an ovulation inhibitor. It has also been used in the palliative treatment of breast cancer.
Megestrol Acetate is the acetate salt form of megestrol, a synthetic derivative of the naturally occurring female sex hormone progesterone with potential anti-estrogenic and antineoplastic activity. Mimicking the action of progesterone, megestrol acetate binds to and activates nuclear progesterone receptors in the reproductive system, and causes the ligand-receptor complex to be translocated to the nucleus where it binds to and promotes expression of target genes. This leads to an alteration in protein synthesis, which modulates cell growth of reproductive tissues. Due to the negative feedback mechanism seen with progesterone, megestrol also blocks luteinizing hormone (LH) release from the pituitary gland, thereby leading to an inhibition of ovulation and an alteration in the cervical mucus and endometrium. Furthermore, without stimulation of LH, estrogen release from the ovaries is stopped, hence impedes the growth of estrogen-sensitive tumor cells.
Megestrol acetate is a progestogen with actions and uses similar to those of the progestogens in general. It also has anti-androgenic properties. It is given by mouth in the palliative treatment or as an adjunct to other therapy in endometrial carcinoma and in breast cancer. Megestrol acetate has been approved to treat anorexia and cachexia. (From Reynolds JEF(Ed): Martindale: The Extra Pharmacopoeia (electronic version). Micromedex, Inc, Englewood, CO, 1995)
See also: Megestrol (has active moiety).

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Drug Indication
For the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Also used for the palliative management of recurrent, inoperable, or metastatic breast cancer, endometrial cancer, and prostate cancer in Canada and some other countries.
FDA Label

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Mechanism of Action
The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time, but its progestin antitumour activity may involve suppression of luteinizing hormone by inhibition of pituitary function. Studies also suggest that the megestrol's weight gain effect is related to its appetite-stimulant or metabolic effects rather than its glucocorticoid-like effects or the production of edema. It has also been suggested that megestrol may alter metabolic pathyways via interferences with the production or action of mediators such as cachectin, a hormone that inhibits adipocyte lipogenic enzymes.

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Pharmacodynamics
Megestrol is a synthetic progestin and has the same physiologic effects as natural progesterone. These effects include induction of secretory changes in the endometrium, increase in basal body temperature, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. Mestrogel has slight glucocorticoid activity and very slight mineralocorticoid activity. This drug has no estrogenic, androgenic, or anabolic activity. The precise mechanism of megestrol’s antianorexic and anticachetic effects is unknown. Initially developed as a contraceptive, it was first evaluated in breast cancer treatment in 1967.

C24H32O4

384.51

384.23

595-33-5

Megestrol acetate-d3;162462-72-8;Megestrol;3562-63-8;Megestrol acetate-d3-1

11683

White to off-white solid powder

1.2±0.1 g/cm3

507.1±50.0 °C at 760 mmHg

214°C

218.5±30.2 °C

0.0±1.3 mmHg at 25°C

1.551

3.82

0

4

3

28

821

6

CC1=C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CC(=O)CC4)C

RQZAXGRLVPAYTJ-GQFGMJRRSA-N

InChI=1S/C24H32O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h12-13,18-20H,6-11H2,1-5H3/t18-,19+,20+,22-,23+,24+/m1/s1

(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,3,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

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)

Solubility in Formulation 1: ≥ 2 mg/mL (5.20 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 20.0 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.

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Solubility in Formulation 2: ≥ 2 mg/mL (5.20 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2 mg/mL (5.20 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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