@Hooker: Exemestane

[sammarbella]

I wonder if you (or other member) could help to understand what that means:

"Exemestane is an irreversible, steroidal aromatase inactivator."

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The maximal suppression evoked by exemestane at the single dose of 25 mg in the present study was similar to published results in postmenopausal women, but the time course differed (24). Evans et al. (24) reported that a single 25-mg oral dose of exemestane maximally suppressed estradiol concentrations by 72% 3 d after administration, and estradiol levels returned to baseline only 8–11 d after drug administration. In the present study maximal suppression of estradiol of 62% was observed 12 h after exemestane administration and returned to baseline 3–6 d after administration. The reason for this difference is not clear, but may be related to the shorter half-life of exemestane in males, the lower exposure to exemestane, and the higher levels of the aromatase substrates androstenedione (1 ng/ml in young males vs. 0.5 ng/ml in postmenopausal women), particularly the much higher testosterone concentrations in young males than in postmenopausal women (700 ng/dl vs. 20 ng/dl, respectively) (25). This is supported by the observation that in the 10-d study in young males reported here, the suppression of estradiol is weaker (due to the very high levels of the precursor testosterone) than that of estrone (due to androstenedione levels not very different from those in postmenopausal women). A limited suppression of circulating estradiol (50%) has been reported in a similar study in young males treated with 1 mg daily anastrozole (7), a dose that reduces estradiol by 85% in postmenopausal women (23)........................

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http://jcem.endojournals.org/cgi/content/full/88/12/5951

If exemestane is an IRREVERSIBLE aromatase INACTIVATOR how could estradiol level come back to normal after 3-6 days exemestane was left?

:confused:

It supress something for ever (even at any %)?

There is a long term effect on bone density (related to low or non present estrogen)?

There are any long term effect?

IRREVERSIBLE and INACTIVATOR are STRONG WORDS when they are related to substances that the body has for a good reason.

I'm about to run a PCT with HCG and exemestane for 2 weeks and a friend of mine advice me on these 2 STRONG WORDS and that make me think about it.

[Bakes]

Hummm, I've done a little bit of research on the topic but it was awhile ago...I'll look into this again and see what I can come up with for you bro.
From what I can see its the extra testosterone in the male body that is the factor here in why the estradiol would come back to "normal" so quickly..
They are comparing it to Arimidex here I see (anastrozole)...where as the exemestane is the generic name for Aromasin. I do know that alot of guys have use Aromasin with great success before and compare it's ability's to to that of Arimidex in that it works in a similar fashion of being an aromatase inhibitor which blocks the estrogen from being made (or converted due to an excess of test such as we require it for). I believe what they mean by "irreversible" is that the drug does not convert to anything else and will continue to do it's function until all of it has been used up in the capacity that it was administered for...
Let me brush up on this topic and get back to this thread, and maybe I will be able to better help answer you're question...

[sammarbella]

Actually i'm taking arimidex with my cycle to prevent aromatase to act and i will use Aromasin(exemestane) during PCT cause it raise testosterone and works well with HCG and Nolva (Arimidex effect is diminished using Nolva at the same time).

My main fear is about the long term sides (if they exist) of short use of exemestane (2-3 weeks periods), i mean permanet loose of any kind of hormone like estrogen or other substances the body need to control cholesterol, bone density, ect.

The thing that i can't understand is why is named as irreversible and inactivator and need to be used during years in cancer breast to have permanent effect(during treatment not after).

In real world IRREVERSIBLE and INACTIVATOR means....IRREVERSIBLE and INACTIVATOR not meantime!

[sammarbella]

Bump!

[sammarbella]

More on this:

http://www.pharm.chula.ac.th/surachai/download/New%20Drugs%201999%20Part%202.pdf

EXEMESTANE (Pharmacia & Upjohn)
Aromasin FDA rating: 1-S, V
Exemestane is a new irreversible aromatase inactivator
that may be used orally to oppose the biological activity
of endogenous estrogen at the subcellular level.
Indications: Exemestane is approved for therapy of
advanced breast cancer in postmenopausal women whose
disease has progressed following tamoxifen therapy.
Pharmacology: Breast cancer cells in some cases
have growth that is estrogen-dependent. Exemestane
inactivates the enzyme aromatase, a key enzyme
required for postmenopausal women to produce
estrogen, which those breast cancer cells need to sur-
vive. Thus, its action depends upon a selective target-
ing and irreversible binding to the molecules of aro-
matase. Indeed, exemestane acts as a “false-sub-
strate.”
Once the binding has occurred, estrogen can no
longer be produced by that enzyme molecule. By inacti-
vation of the aromatase enzyme, exemestane reduces the
supply of estrogen to cancerous cells and consequently
prevents them from continuing to grow. This method of
action as an inactivator of aromatase differs from the
action of previous aromatase inhibitors because it binds
irreversibly to the aromatase enzyme molecules, pro-
ducing a permanent rather than temporary disruption
of their function.This significantly lowers circulating
estrogens without altering glucocorticoid or mineralo-
corticoid levels.
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http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed6.section.16133

Exemestane


Exemestane (6-methylene-androsta-1,4-diene-3,17-dione, Aromasin) is an irreversible (type I or mechanism-based) aromatase inhibitor.3941 Its Ki for competitive inhibition is 10.2 nmol/L, and for irreversible inactivation, it is 26 nmol/L. Single-dose administration reveals a major reduction of plasma estrogens with this compound.41 A dose of 25 mg/d inhibited aromatase activity as documented by the isotope kinetic technique by 97.9%. Phase II clinical trials of exemestane in postmenopausal patients with metastatic breast cancer showed very promising results with response rates ranging from 11 to 28%, depending on the extent of prior endocrine therapy.42,43 In a large, randomized phase III trial conducted in postmenopausal patients with metastatic breast cancer no longer responding to tamoxifen, exemestane 25 mg PO daily was compared to megestrol acetate 40 mg qid. This multicenter international trial enrolled 769 patients. Patient and disease characteristics were equally distributed between the two arms of the trial. Kaufman and colleagues reported a 15% objective response rate among the 366 women receiving exemestane, which was similar to the 12.4% response rate for the women treated with megestrol acetate. An additional 22% of women in each treatment group experienced stabilization of their disease. Exemestane produced a statistically significant increase in the median duration of overall clinical benefit (60.1 versus 49 weeks, p = .025) as well as in the median time to tumor progression. Furthermore, in this trial, the authors reported that the median survival was also significantly longer in patients receiving exemestane. Table 64-1 summarizes these results. Side effects associated with exemestane treatment were mild and included hot flashes, nausea, and fatigue in a relatively few patients. Undesirable weight gain was also less frequent among women receiving exemestane, compared with that observed in women treated with megestrol acetate.44
Clinical Pharmacology and Pharmacokinetics


Both anastrozole (Arimidex: ICI-D-1033; 2,2 [5-(1H-1,2,4-Triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile) and letrozole (Femara: 4,4-(1H-1,2,4-Triazol-1-ylmethylene)-bisbenzonitrile) are nonsteroidal aromatase inhibitors, whereas exemestane has a steroidal structure. Exemestane has androgenic properties and its use is associated with steroidal-like side effects such as weight gain and acne.4547

Anastrozole, letrozole, and exemestane display differences in their pharmacokinetic and pharmacodynamic properties. Anastrozole and letrozole bind reversibly to the aromatase enzyme (and are classed as type II nonsteroidal aromatase inhibitors),48 whereas exemestane binds irreversibly causing permanent inactivation of the aromatase enzyme, even after the drug is cleared from the circulation (classed as type I steroidal aromatase inhibitors).48 The clinical relevance of these differences in mechanism of action, if any, remains to be established.

Anastrozole, letrozole, and exemestane are each given orally at once-daily doses of 1 mg, 2.5 mg, and 25 mg, respectively. The time taken to reach maximal estradiol (E2) suppression for anastrozole and letrozole is 2 to 4 days,49,50 as compared to 7 days for exemestane.51 However, it should be noted that Zilembo and colleagues51 only took measurements every 7 days and it is not known whether maximal E2 suppression following exemestane occurred before this. Whether these differences have any impact on the onset of therapeutic action remains to be established.

Anastrozole and exemestane both attain steady-state dosing conditions by 7 days.52,53 In contrast, letrozole reportedly takes 60 days to achieve steady-state plasma levels,54 which may be reflective of the accumulation that occurs with letrozole over long-term dosing.55 In this study, when compared to the mean letrozole concentration of 44.6 nmol/L reported after 14 days of letrozole treatment, there was a 25% (55.8 nmol/L), 29% (57.6 nmol/L) and 34% (59.7 nmol/L) increase in the mean plasma letrozole levels following 28, 56, and 84 days of treatment, respectively.55 These results suggest a nonlinear relationship between the dose and the efficacy of letrozole. The half-lives of anastrozole (1 mg) and exemestane (25 mg) are 4156 and 27 h,57 respectively, whereas for letrozole (2.5 mg) it is reported to be up to 4 days.58,59

It has been established from monitoring the plasma levels of estrogen in women with breast cancer that aromatase inhibitors effectively reduce plasma E2, estrone (E1), and estrone sulphate (E1S), by 81 to 94% for anastrozole,60,61 88 to 98% for letrozole,61 and 52 to 72% for exemestane.46,51 One study comparing the extent of plasma E1, E1S, and E2 suppression following 6 weeks treatment with either anastrozole or letrozole in postmenopausal women with metastatic breast cancer61 found that anastrozole and letrozole reduced plasma E2 by 84.9% and 87.8%, respectively (no significant differences between the groups). Anastrozole and letrozole reduced E1 levels by 81.0% and 84.3%, respectively, although the extent of this suppression was significantly greater in the letrozole group (p = .019). Anastrozole and letrozole reduced plasma E1S levels by 93.5% and 98.0%, respectively, with the extent of this suppression being significantly greater in the letrozole group when compared to the anastrozole group (p = .019). It is not known whether this small increase in potency seen with letrozole has any clinical impact. In a separate study, exemestane treatment was found to suppress plasma E2 levels when compared to baseline by 65%.51

Separate studies confirm that anastrozole, letrozole, and exemestane all reduce tumor estrogens, but differences in the way that these data are presented make it difficult to assess whether one agent is more potent than another.6264 A small study by Geisler and colleagues62 reported that in 14 postmenopausal women with locally advanced breast cancer, 15 weeks of treatment with anastrozole (1 mg qd) reduced E2, E1, and E1S within breast tumors by 88.1%, 83%, and 73%, respectively. Three months of treatment with letrozole (2.5 mg qd) was reported to significantly (p = .02) reduce estrogen concentrations in 11 postmenopausal women with hormone-receptor-positive breast tumors.63 Exemestane treatment (25 mg qd) for 3 months was also reported to "profoundly reduce" estrogen within breast tumors in 11 postmenopausal women with hormone-receptor-positive breast tumors, although the significance value was not stated.64 Levels of the aromatase enzyme within the tumor are also reduced by anastrozole, letrozole, and exemestane, with all three agents resulting in reductions of a similar degree (97 to 98%).6264

Anastrozole inhibits (in decreasing order of magnitude) CYP1A2, CYP2C8/9, and CYP3A4,65 having no effect on CYP2A6 or CYP2D6; letrozole strongly inhibits CYP2A6, moderately inhibits CYP2C19, and has a low affinity for CYP3A4;66 and exemestane is metabolized by CYP3A4.67 Thus, there is potential for drug-drug interactions if patients are prescribed concomitant medication that interacts with these cytochrome P450 enzymes. Anastrozole nor letrozole interact with cimetidine (a marker for CYP3A4 activity)65,66 or warfarin (a marker for CYP3A4 and CYP1A2 activity).65,66,68 To date, no formal drug-drug interaction studies have been reported for exemestane, although the potential for drug-drug interactions is only likely to arise for drugs affecting CYP3A4.

Tamoxifen interacts with both anastrozole and letrozole. Lower plasma levels of anastrozole have been observed when administered in combination with tamoxifen (mean decrease in the plasma minimum concentration [Cmin] of 27%; 90% CI, 20 to 30%).69 This interaction did not appear to impact upon E2 suppression expected with anastrozole.

Letrozole also interacts with tamoxifen (mean decrease in Cmin of 38%; 90% CI, 32 to 43%),70 but to a greater extent than is seen with the anastrozole/tamoxifen combination. However, the reduction in levels of letrozole in combination with tamoxifen does not appear to alter E2 suppression by aromatase inhibition.70

Anastrozole and letrozole have no androgenic, progestogenic, or estrogenic effects such as weight gain, acne, and hypertrichosis; although generally associated with supratherapeutic doses, these effects have been reported in patients receiving the approved clinical dose of exemestane.4547

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[sammarbella]

More info i found, more confuse i am. :confused:

"This method of action as an inactivator of aromatase differs from the
action of previous aromatase inhibitors because it binds
irreversibly to the aromatase enzyme molecules, pro-
ducing a permanent rather than temporary disruption
of their function."

If the action of exemestane is a bound between itself and aromatase enzyme inactivating it, how could it exert its action AFTER we leave the treatment?

:confused:

"exemestane binds irreversibly causing permanent inactivation of the aromatase enzyme, even after the drug is cleared from the circulation (classed as type I steroidal aromatase inhibitors).48 The clinical relevance of these differences in mechanism of action, if any, remains to be established."

:confused:

If the drug is cleared from the circulation (no more exemestane "supply") what actually bind the new produced and not bounded aromatase enzyme???

This is a nonsense for me that the inhibition could be permanent and need to be "on" exemestane to exert his action.(If it was really permanet why they need to take it for years?)

[hooker]

I don't log in daily, but even though it's been answered already, I'll tell you:

Aromasin is "irreversible" because it's a type-I Aromatase Inhibitor. It inactivates the aromatase enzyme it binds to permanently. Even if you take away the aromasin, that enzyme is not going to create estrogen from testosterone any longer. Your body can still produce more of the aromatase ezyme though, although the ones Aromasin attached to are never going to be functional again- the new ones your body produces will take the place (eventually) of the ones inactivated permanently by the Aromasin.

For a type-II AI to work, it actually has to be present in the blood. This is a "reversible" inhibitor. When it detaches from the aromatase enzyme, that enzyme begins to function again and has the ability to convert testosterone into estrogen.

Kudos to everyone in this thread who contributed, though. Good answers all around.