Aromatase (IC50s = 30 nM)

Exemestane dramatically boosts the number of cells in hFOB, Saos-2 cells (1-1000 nM; 72 h) [2]. Exemestane (72 h) stimulates the expression of MYBL2, OSTM1, HOXD11, ADCYAP1R1, and glypican 2 in hFOB cells and boosts alkaline phosphatase activity in Saos-2 and hFOB cells [2]. With a Ki of 4.3 nM, exemestane competitively inhibits and inactivates human placental aromatase in a time-dependent manner. With an IC50 of 0.9 μM, exemestane substitutes [3H]5α-dihydrotestosterone in the rat prostate androgen receptor [1].

Treatment with exemestane (20–100 mg/kg; intramuscular injection; once weekly; for 16 weeks) resulted in significant increases in trabecular bone volume, fifth lumbar vertebra compressive strength, femoral flexural strength, and lumbar and femoral BMD. Exemestane considerably lowers the elevations in serum osteocalcin and pyridinoline that are brought on by ovariectomy. Serum cholesterol and LDL cholesterol are markedly lowered with exemestane [3]. Rats with mammary tumors produced by 7,12-dimethylbenzanthracene (DMBA) show 26% complete (CR) and 18% partial (PR) tumor regression when exposed to exemestane (20 mg/kg/day) subcutaneously [4].
When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.[1]

Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17 beta-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5 alpha-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively[1].

Cell Viability Assay[2]
Cell Types: hFOB, Saos-2 cells
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1000 nM
Incubation Duration: 72 hrs (hours)
Experimental Results: Induced cell proliferation.

Animal/Disease Models: Female Sprague Dawley rats (10-month-old) bearing ovariectomy [3]
Doses: 20 mg/kg, 50 mg/kg, or 100 mg/kg
Route of Administration: intramuscular (im) injection; once weekly; for 16 weeks
Experimental Results: Dramatically increased the lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume.

Absorption, Distribution and Excretion
42%
Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.
The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.
Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng·hr/mL) were about twice those in healthy women (41.4 ng·hr/mL).
Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and (alpha) 1 -acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.
For more Absorption, Distribution and Excretion (Complete) data for EXEMESTANE (11 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Hepatic
Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

---

Biological Half-Life
24 hours
Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours.
... The terminal half-life was 8.9 hr. Maximal estradiol suppression of 62 +/- 14% was observed at 12 hr.

Hepatotoxicity
Serum enzymes are reported to be elevated in 4% to 11% of women treated with exemestane, but these elevations are usually mild, asymptomatic and self-limited, rarely requiring dose modification. There have been very rare instances of clinically apparent liver injury associated with exemestane therapy, typically arising withinone to four months of starting treatment and typically presenting with a cholestatic pattern of enzyme elevations. Immunoallergic features (fever, rash, eosinophilia) are uncommon as are autoantibody formation. Some instances have been severe with signs of hepatic failure, but most cases were self-limited. Unlike tamoxifen, exemestane has not been associated with development of fatty liver disease, steatohepatitis or cirrhosis.
Likelihood score: C (probable cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of exemestane during breastfeeding. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. The manufacturer recommends that breastfeeding be discontinued during exemestane therapy and for 1 month after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
90% (mainly α1-acid glycoprotein and albumin)

[1]. Novel aromatase and 5 alpha-reductase inhibitors. J Steroid Biochem Mol Biol, 1994. 49(4-6): p. 289-94.

[2]. Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2004 Sep 1;10(17):5717-23.

[3]. Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res, 2004. 10(17): p. 5717-23.

[4]. Zaccheo, T., D. Giudici, and E. Di Salle, Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats. J Steroid Biochem Mol Biol, 1993. 44(4-6): p. 677-80.

Exemestane is a 17-oxo steroid that is androsta-1,4-diene-3,17-dione in which the hydrogens at position 6 are replaced by a double bond to a methylene group. A selective inhibitor of the aromatase (oestrogen synthase) system, it is used in the treatment of advanced breast cancer. It has a role as an EC 1.14.14.14 (aromatase) inhibitor, an antineoplastic agent, an environmental contaminant and a xenobiotic. It is a 17-oxo steroid and a 3-oxo-Delta(1),Delta(4)-steroid. It derives from a hydride of an androstane.
Exemestane is an oral steroidal aromatase inhibitor used in the adjuvant treatment of hormonally-responsive (also called hormone-receptor-positive, estrogen-responsive) breast cancer in postmenopausal women. It irreversibly binds to the active site of the enzyme resulting in permanent inhibition.
Exemestane is an Aromatase Inhibitor. The mechanism of action of exemestane is as an Aromatase Inhibitor.
Exemestane is a steroidal inhibitor of aromatase which effectively blocks estrogen synthesis in postmenopausal women and is used as therapy of estrogen receptor positive breast cancer, usually after resection and after failure of tamoxifen. Exemestane has been associated with a low rate of serum enzyme elevations during therapy and rare instances of clinically apparent liver injury.
Exemestane is an irreversible steroidal aromatase inhibitor, with antiestrogen and antineoplastic activities. Upon oral administration, exemestane binds irreversibly to and inhibits the enzyme aromatase, thereby blocking the peripheral aromatization of androgens, including androstenedione and testosterone, to estrogens. This lowers estrogen levels in the blood circulation.

---

Drug Indication
For the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
FDA Label

---

Mechanism of Action
Breast cancer cell growth may be estrogen-dependent. Aromatase (exemestane) is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It irreversibly binds to the active site causing permanent inhibition necessitating de novo synthesis to restore enzymatic function. Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on the adrenal biosynthesis of corticosteroids or aldosterone. This reduction in serum and tumor concentrations of estrogen delays tumor growth and disease progression. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
... exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors...
Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
... Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total aromatase inhibition in vivo with the use of a steroidal aromatase inhibitor. The observation that exemestane is a highly potent aromatase inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer.
... Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S(35)-methionine was used to determine the half-life (t(1/2)) of aromatase protein. In the presence of 200 nmol/L exemestane, the t(1/2) of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. ...

C20H24O2

296.4

296.177

C, 81.04; H, 8.16; O, 10.80

107868-30-4

Exemestane (Standard);107868-30-4;Exemestane-d2;Exemestane-13C3;Exemestane-d3

60198

... white to slightly yellow crystalline powder

1.1±0.1 g/cm3

453.7±45.0 °C at 760 mmHg

155.13°C

169.0±25.7 °C

0.0±1.1 mmHg at 25°C

1.572

3.11

0

2

0

22

653

5

O=C1C([H])([H])C([H])([H])[C@]2([H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])[C@]1([H])[C@]3(C([H])=C([H])C(C([H])=C3C(=C([H])[H])C([H])([H])[C@@]21[H])=O)C([H])([H])[H]

BFYIZQONLCFLEV-DAELLWKTSA-N

InChI=1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1

(8R,9S,10R,13S,14S)-10,13-dimethyl-6-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione.

FCE24304, PNU155971; PNU155971; PNU-155971; PNU 155971; FCE24304; FCE-24304; FCE 24304; Exemestane; US trade name: Aromasin.

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: ≥ 2.5 mg/mL (8.43 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 25.0 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.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (8.43 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 25.0 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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (8.43 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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