MEGESTROL

First approved in 1971

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H30O3
Molecular Weight	342.4718
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CC[C@](O)(C(C)=O)[C@@]1(C)CC[C@@]3([H])[C@@]2([H])C=C(C)C4=CC(=O)CC[C@]34C

InChI

InChIKey=VXIMPSPISRVBPZ-NWUMPJBXSA-N

InChI=1S/C22H30O3/c1-13-11-16-17(20(3)8-5-15(24)12-19(13)20)6-9-21(4)18(16)7-10-22(21,25)14(2)23/h11-12,16-18,25H,5-10H2,1-4H3/t16-,17+,18+,20-,21+,22+/m1/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/?term=23395103

Megestrol acetate is 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. MEGACE Oral Suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). 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. The major route of drug elimination in humans is urine. When radiolabeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5% to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7% to 30.3% (mean 19.8%). The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%). Megestrol acetate 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. Plasma steady-state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of MEGACE Oral Suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Progesterone receptor 61 Target ID: CHEMBL208 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15086241	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Anorexia 5 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf	Palliative		Approved 8429	MEGACE Approved Use Megestrol acetate oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Launch Date 1993
Cachexia 8 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf	Palliative		Approved 8429	MEGACE Approved Use Megestrol acetate oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Launch Date 1993

C_max

Value	Dose	Analyte	Population
753 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021778s002s003lbl.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
490 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021778s002s003lbl.pdf	750 mg 1 times / day steady-state, oral dose: 750 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
1133 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1618 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
1364 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
187 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
10476 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021778s002s003lbl.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
6779 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021778s002s003lbl.pdf	750 mg 1 times / day steady-state, oral dose: 750 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
12095 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
16268 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
18625 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
8942 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
33.68 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
39.75 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	625 mg single, oral dose: 625 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
32.84 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
31.38 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19774117/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	MEGESTROL ACETATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
400 mg 2 times / day multiple, oral Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15595341	unhealthy, 54-68 years n = 2 Health Status: unhealthy Age Group: 54-68 years Sex: F Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/15595341	Disc. AE: Osteoporosis... AEs leading to discontinuation/dose reduction: Osteoporosis (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/15595341
625 mg 1 times / day multiple, oral Recommended Dose: 625 mg, 1 times / day Route: oral Route: multiple Dose: 625 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27218795	unhealthy, 65 years n = 1 Health Status: unhealthy Age Group: 65 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/27218795	Disc. AE: Adrenal insufficiency... AEs leading to discontinuation/dose reduction: Adrenal insufficiency (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/27218795
40 mg 2 times / day multiple, oral Dose: 40 mg, 2 times / day Route: oral Route: multiple Dose: 40 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	unhealthy, 85 years n = 1 Health Status: unhealthy Condition: Alzheimer's disease Age Group: 85 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	Disc. AE: Deep vein thrombosis... AEs leading to discontinuation/dose reduction: Deep vein thrombosis (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/16563066
400 mg 2 times / day multiple, oral Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	unhealthy, 86 years n = 1 Health Status: unhealthy Condition: Alzheimer's disease Age Group: 86 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	Disc. AE: Deep vein thrombosis... AEs leading to discontinuation/dose reduction: Deep vein thrombosis (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/16563066
1600 mg 1 times / day multiple, oral Highest studied dose Dose: 1600 mg, 1 times / day Route: oral Route: multiple Dose: 1600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3368800	unhealthy Health Status: unhealthy Condition: advanced breast cancer Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/3368800	Sources: https://pubmed.ncbi.nlm.nih.gov/3368800

AEs

AE	Significance	Dose	Population
Osteoporosis	2 patients Disc. AE	400 mg 2 times / day multiple, oral Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15595341	unhealthy, 54-68 years n = 2 Health Status: unhealthy Age Group: 54-68 years Sex: F Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/15595341
Adrenal insufficiency	1 patient Disc. AE	625 mg 1 times / day multiple, oral Recommended Dose: 625 mg, 1 times / day Route: oral Route: multiple Dose: 625 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27218795	unhealthy, 65 years n = 1 Health Status: unhealthy Age Group: 65 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/27218795
Deep vein thrombosis	1 patient Disc. AE	40 mg 2 times / day multiple, oral Dose: 40 mg, 2 times / day Route: oral Route: multiple Dose: 40 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	unhealthy, 85 years n = 1 Health Status: unhealthy Condition: Alzheimer's disease Age Group: 85 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/16563066
Deep vein thrombosis	1 patient Disc. AE	400 mg 2 times / day multiple, oral Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/16563066	unhealthy, 86 years n = 1 Health Status: unhealthy Condition: Alzheimer's disease Age Group: 86 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/16563066

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781 substrate 1737	inhibitor 1767 inducer 389 substrate 1037	inhibitor 1852 substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2A6 707 CYP2C19 1478	CYP3A5 395 CYP1A2 1054 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2C19 991 CYP2E1 667 CYP4A11 119	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	mild [Inhibition 50 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	mild [Inhibition 50 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	moderate [Inhibition 50 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	moderate [Inhibition 50 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=14 Page: 14.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=14 Page: 14.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=14 Page: 14.0	no
CYP1A2 1692	activator 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	yes [Activation 50 uM]
CYP2E1 970	activator 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	yes [Activation 50 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021778s000_ClinPharmR.pdf#page=13 Page: 13.0	yes [Inhibition 50 uM]

Drug as victim

Target	Modality	Activity
CYP1A2 1054	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2A6 543	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2B6 664	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2C19 991	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2C8 693	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2C9 1037	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2D6 1217	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP2E1 667	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP4A11 119	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	no
CYP3A4 1737	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	yes
CYP3A5 395	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129397/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:6722	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:6722
ZINC	ZINC000033902346	http://zinc15.docking.org/substances/ZINC000033902346

PubMed

Title	Date	PubMed
Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors.	2001 Apr 6	11286465
A comparison of megestrol acetate, nandrolone decanoate and dietary counselling for HIV associated weight loss.	2001 Aug	11454075
Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882).	2001 Feb	11232948
Cost-effectiveness analysis of exemestane compared with megestrol in patients with advanced breast carcinoma.	2001 Feb 1	11169930
Efficacy and economics of hormonal therapies for advanced breast cancer.	2002	12149051
The impact of hormonal treatments on quality of life of patients with metastatic breast cancer.	2002	12117073
Variant estrogen receptors and their role in liver disease.	2002 Jul 31	12161003
Effect of megestrol caproate on the reproductive function of laboratory animals.	2002 Jun	12447469
Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study.	2002 Jun	12123333
[Low-grade sarcoma of the endometrial stroma: late recurrence with ureteral and bladder involvement].	2002 Oct	12455286
Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays.	2002 Oct 29	12388792
Phase I and pharmacokinetic study of vinblastine and high-dose megestrol acetate.	2002 Sep	12203099
Megestrol complications.	2003 Jan	12527643
Postmenopausal femur bone loss: effects of a low dose hormone replacement therapy.	2003 Jul 25	12818462
Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate.	2003 Jul-Aug	12926095
[Effects of a 19-norprogesterone derivative, the fourth decade nomegestrol acetate, on lipids].	2003 Jun	12910065
An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.	2003 Nov	14672731
Economic evaluation of antiaromatase agents in the second-line treatment of metastatic breast cancer.	2003 Nov	12883965
Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy.	2004	14680484
[Nome gesrol (lutenyl) induced severe acute hepatitis].	2004 Jan	15041823
Therapy for unresectable hepatocellular carcinoma: review of the randomized clinical trials-II: systemic and local non-embolization-based therapies in unresectable and advanced hepatocellular carcinoma.	2004 Jun	15166617
Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies.	2005	15987448
The effects of aromatase inhibitors on lipids and thrombosis.	2005 Aug	16100522
Pregnancy following intracytoplasmic sperm injection and preimplantation genetic diagnosis after the conservative management of endometrial cancer.	2005 Jun	15970008
Review of cost-effectiveness analyses in hormonal therapies in advanced breast cancer.	2005 Sep	16144501
Bleeding patterns during continuous estradiol with different sequential progestogens therapy.	2005 Sep-Oct	16145305
Progestogens: effects on clinical and biochemical parameters in postmenopausal women.	2005 Sep-Oct	16145299
Effects of a single Silastic contraceptive implant containing nomegestrol acetate (Uniplant) on endometrial morphology and ovarian function for 1 year.	2006 Dec	17157108
A successful live birth through in vitro fertilization program after conservative treatment of FIGO grade I endometrial cancer.	2006 Jun	16778408
Characterization of related impurities in megestrol acetate.	2006 Jun 16	16616448
[Pharmacological therapy of cancer anorexia-cachexia].	2006 May	16768027
Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate.	2006 Oct	17012461
Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: a randomized, double-blind, placebo-controlled, multicenter trial.	2007 Feb	17090640
Longitudinal evaluation of serum leptin and bone mineral density in early postmenopausal women.	2007 May-Jun	17242633

Patents

Sample Use Guides

In Vivo Use Guide

Oral Suspension is 800 mg/day (20 mL/day). In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day.

Route of Administration: Oral

In Vitro Use Guide

Megestrol acetate was shown to inhibit the growth of HepG2 cells in vitro in dose- and time-dependent manners with an IC (50) of 260 uM (24-h incubation)

Name

Type

Language

MEGESTROL

Official Name

English

MEGESTROL ACETATE IMPURITY B [EP IMPURITY]

Common Name

English

MEGESTROL [VANDF]

Common Name

English

MEGESTROL [HSDB]

Common Name

English

Megestrol [WHO-DD]

Common Name

English

17-HYDROXY-6-METHYLPREGNA-4,6-DIENE-3,20-DIONE

Systematic Name

English

CHRONOPIL

Brand Name

English

megestrol [INN]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QG03AC05