Formestane

Các tên gọi khác (11 ) :

4-hydroxy-4-androstene-3,17-dione
4-Hydroxy-delta(4)-androstenedione
4-hydroxy-Δ4-androstenedione
4-hydroxyandrostenedione
4-OH-A
4-OHAD
CGP 32349
CGP-32349
Formestano
Formestanum
Lentaron

Thuốc điều trị ung thư

Thuốc Gốc

Small Molecule

CAS: 566-48-3

ATC: L02BG02

CTHH: C₁₉H₂₆O₃

PTK: 302.4079

Formestane was the first selective, type I, steroidal aromatase inhibitor used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. Formestane suppresses estrogen production from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a mild aromatase inhibitor. It is listed as a prohibited substance by the World Anti-Doping Agency for use in athletes. Formestane has poor oral bioavailability, and thus must be administered forthnightly (bi-weekly) by intramuscular injection. Some clinical data has suggested that the clinically recommended dose of 250mg was too low. With the discovery of newer, non-steroidal and steroidal, aromatase inhibitors which were orally active and less expensive than formestane, formestane lost popularity. Currently, formestane (categorized as an anti-estrogenic agent) is prohibited from use in sports in accordance to the regulations of the World Anti-Doping Agency. It is not US FDA approved, and the intramuscular injection form of formestane (Lentaron) which was approved in Europe has been withdrawn.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₁₉H₂₆O₃

Phân tử khối

302.4079

Monoisotopic mass

302.188194698

InChI

InChI=1S/C19H26O3/c1-18-10-8-15(20)17(22)14(18)4-3-11-12-5-6-16(21)19(12,2)9-7-13(11)18/h11-13,22H,3-10H2,1-2H3/t11-,12-,13-,18+,19-/m0/s1

InChI Key

InChIKey=OSVMTWJCGUFAOD-KZQROQTASA-N

IUPAC Name

(1S,2R,10R,11S,15S)-6-hydroxy-2,15-dimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadec-6-ene-5,14-dione

Traditional IUPAC Name

formestane

SMILES

[H][C@@]12CCC(=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=C(O)C(=O)CC[C@]12C

Độ tan chảy

199 - 202

Độ hòa tan

Insoluble

logP

2.66

logS

-3.7

pKa (strongest acidic)

9.21

pKa (Strongest Basic)

-3.7

PSA

54.37 Å²

Refractivity

85.57 m³·mol^-1

Polarizability

34.07 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

pKa

9.31

Dược Lực Học : By significantly reducing estrogen levels in the bloodstream, formestane may exhibit antitumor activity. In one trial involving 147 postmenopausal females with advanced breast cancers resistant to standard therapies, 22% of patients achieved a partial response, while another 20% achieved disease stabilization. [3] In comparative trials comparing a non-steroidal aromatase inhibitor, anastrozole, with formestane, it was found that anastrozole was more effective and consistent at suppressing estrogen levels in the body. However, these results were of unverified clinical significance. [5]

Cơ Chế Tác Dụng : Formestane was the first selective, type I, steroidal aromatase inhibitor used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. Formestane suppresses estrogen production from anabolic steroids or prohormones. It also acts as a prohormone to 4-hydroxytestosterone, an active steroid which displays weak androgenic activity in addition to acting as a mild aromatase inhibitor. It is listed as a prohibited substance by the World Anti-Doping Agency for use in athletes. Formestane has poor oral bioavailability, and thus must be administered forthnightly (bi-weekly) by intramuscular injection. Some clinical data has suggested that the clinically recommended dose of 250mg was too low. With the discovery of newer, non-steroidal and steroidal, aromatase inhibitors which were orally active and less expensive than formestane, formestane lost popularity. Currently, formestane (categorized as an anti-estrogenic agent) is prohibited from use in sports in accordance to the regulations of the World Anti-Doping Agency. It is not US FDA approved, and the intramuscular injection form of formestane (Lentaron) which was approved in Europe has been withdrawn. Formestane is a second generation, irreversible, steroidal aromatase inhibitor. It inhibits the aromatase enzyme responsible for converting androgens to estrogens, thereby preventing estrogen production. Breast cancer may be estrogen sensitive or insensitive. A majority of breast cancers are estrogen sensitive. Estrogen sensitive breast cancer cells depend on estrogen for viability. Thus removal of estrogen from the body can be an effective treatment for hormone sensitive breast cancers. Formestane has been targeted specifically for the treatment of postmenopausal women. Unlike premenopausal women who produce most estrogen in the ovaries, postmenopausal women produce most estrogen in peripheral tissues with the help of the aromatase enzyme. Formestane, an aromatase inhibitor, can thus help to decrease the local production of estrogen by blocking the aromatase enzyme in peripheral tissues (ie. adispose tissue of the breast) to treat hormone sensitive breast cancer.

Dược Động Học :

▧ Absorption :
Formestane has poor oral bioavailability, but is fully bioavailable when administered via the established intramuscular route. The AUC after an intravenous pulse dose does not vary considerably from that of an intramuscular dose. Within 24-48 h of the first dose of intramuscular formestane, a C(max) of 48.0 +/- 20.9 nmol/l was achieved in one study. [2]
▧ Volume of Distribution :
Vd = 1.8 L/kg; widely distributed to organs and tissues when delivered intravenously. [2]
▧ Metabolism :
Hepatic metabolism. Phase I of metabolism is mainly reductive in nature. The reduction products 3 beta-hydroxy-5alpha-androstane-4,17-dione and 3alpha-hydroxy-5beta-androstane-4,17-dione are produced, and further reduced. A notable step in the process of metabolism is a keto reduction on carbon number three of the molecule. The main metabolite which is produced from formestane is 4-hydroyxyandrost-4-ene-3,17-dione-4-glucuronide. The oxidation products identified were 4-hydroxyandrosta-4,6-diene-3,17-dione and 4-hydroxyandrosta-1,4-diene-3,17-dione. In phase II, conjugation was diverse and included sulfatation and glucuronidation. 4-hydroxytestosterone, the 17-hydroxylated analog to formestane, was identified as one particular metabolite found in women's urine. This finding was the result of an oral administration of 500mg of formestane in women.
▧ Route of Elimination :
Renal elimination. >95% in urine, <5% in feces.
▧ Half Life :
Terminal plasma elimination half life of 18 minutes, when delivered intravenously. [2]
▧ Clearance :
Plasma clearance is approximately 4.2 L/(h kg), when delivered intravenously. In women, following a 500mg dose of formestane, 20% was excreted as glucuronide within the first 24 hours. [1] One long term metabolite (3beta,4alpha-dihydroxy-5alpha-androstan-17-one) can be detected for 90 hours. A longer detection time is possible with more sensitive technology, which may be of utility in sports drug testing. [1]

Chỉ Định : For the treatment of estrogen-receptor positive breast cancer in post-menopausal women.

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty :

Sản phẩm biệt dược : Lentaron

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB08905

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D07260

Wikipedia

http://en.wikipedia.org/wiki/Formestane

Drugs.com

http://www.drugs.com/international/formestane.html

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