Ethinyl Estradiol

PubChem CID

5991

ECHA InfoCard

• 100.000.311
• EC / List #: 200-32-2

IUPHAR/BPS

7071

DrugBank Accession Number

DB00977

UNII

423D2T571U

KEGG Entry Number

D00554

Wikipedia Entry Name

Ethinylestradiol

ChEBI ID

CHEBI:4903

ChEMBL ID

CHEMBL691

ChemSpider ID

5770

PDB

Ethinyl Estradiol

NIST

Ethinyl Estradiol

ATC Code(s)

• G03CA01
• L02AA03

Appearance

White or slightly yellowish-white, crystalline powder

Melting Point

180-186 °C (if polymorphic modification: 142-146 °C)

Solubility

BP: practically insoluble in water.
PubChem: 11.3 mg/L water at 27 °C.
PubChem, BP: 1 part in 6 of ethanol, 1 in 4 of ether, 1 in 5 of acetone, 1 in 4 of dioxane, and 1 in 20 of chloroform. Soluble in vegetable oils, and in solutions of fixed alkali hydroxides (e.g. NaOH, KOH)

logP

3.67

Specific Optical Rotation

Pubchem/Toxnet: [3.5°] at 24° C/D (c = 2 in dioxane); [-29.5°] at 24° C/D (c = 2 in pyridine)
USP: -28° to -29.5°, 50 mg/mL in colorless pyridine from a freshly opened container

Vapor Pressure

1.95x10^-9 mm Hg at 25° C (est)

Henry's Law Constant

7.94x10^-12 atm-cu m/mol at 25° C (est.)

Polymorphism

Yes

Storage Conditions

Protect from light

GHS Hazard Code(s)

Side Effects

Adverse effects attributed to estrogenic and metabolic effects. Water and sodium retention, which may lead to weight gain, edema, and tender breast enlargement. Changes in libido and withdrawal vaginal bleeding. Liver function impairment, jaundice, and gallstones may occur. Headache, depression, dizziness, glucose intolerance, and a sensitivity to contact lenses have been reported. Nausea, vomiting and break through vaginal bleeding are not uncommon. Dermatological effects include chloasma, melasma, rashes, and urticaria. Erytheme multiforme and erytheme nodosum occur. Hypertension and thromoboembolic disease are reported.
Ortho Evra adverse effects: breast symptoms, headache, application site reaction, nausea, upper respiratory infection, menstrual cramps, abdominal pain.

Carcinogenicity

There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy.

Mutagenicity

Not found to be mutagenic in the Ames Salmonella/microsome direct plate incorporation protocol.

Genotoxicity

Not found to be genotoxic in human lymphocyte assay in vitro and mouse bone marrow micronucleus test in vivo.

LD₅₀

• mouse intraperitoneal: 0.250 g/kg
• mouse oral: 0.950 g/kg (ChemIDPlus), 1737 mg/kg (PubChem)
• mouse subcutaneous: > 3 g/kg
• rat intraperitoneal: 0.471 g/kg
• rat oral: 0.960 g/kg (PubChem: 1200 mg/kg and > 5000 mg/kg)
• rat subcutaneous: > 2 g/kg

TD_Lo

human women: 0.21 mg/kg/21 days

TD₅₀

rat, hepatic tumor: 0.2 mg/kg/day

MRTD

0.0005 mg/kg/day

Estrogen Receptor Activity

Agonist

Bioavailability

• Oral: Around 45%
• Vaginal Ring: 55%

Elimination Half-Life (t_1/2)

• PubChem: 13-27 h (35 μg ethinyl estradiol with 1 mg norethindrone)
• 7.7 h (single oral dose)
• PubChem: 36 +/- 13 h

Serum Protein Binding

97% bound. Mainly to serum albumin. No binding to SHBG, but induces SHBG synthesis.

Metabolism

Metabolized by CYP3A4, CYP2C9, UGT

Excretion

Primarily in urine with sulfate and glucuronide conjugates. Some fecal excretion. Very small amounts excreted in milk.

T_max

2-3 h

Enzyme Interactions

• Inhibits CYP2C9, CYP2C19, CYP3A4, CYP2B6
• After formation of very reactive intermediate by oxidation of C17 ethinyl, can irreversibly inhibit cytochrome P450 enzymes (e.g. CYP2C8, CYP3A4). Thus it exerts strong effects on hepatic metabolism.
• Nuclear receptor subfamily 1 group I member 2: agonist
• Bile salt export pump: inhibitor, inducer
• Sodium/bile acid cotransporter: inducer
• Canalicular multispecific organic anion transporter 1: inducer
• Multidrug resistance protein 1: substrate
• Uridine diphosphate glucuronosyltransferase (UGT): inducer

Indications

For treatment of moderate to severe vasomotor symptoms associated with menopause, female hypogonadism, prostatic carcinoma-palliative therapy of advanced disease, breast cancer, as an oral contraceptive, and as emergency contraceptive.