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Poor Oral Formestane Bioavailability - Myth?

Royd The Noyd

Royd The Noyd

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Why is it that people think oral formestane has such poor bioavailability. The below reference [1] finds that in women there is no difference in serum estradiol levels between a 250mg dose and a 500mg dose. Estrone was suppressed by all doses.


It should be noted that men likely require about a 15% higher dose simply because we metabolize (glucoronidation) formestane to a higher degree [2-3].


Is there research I am missing? If not, why mess with transdermals? Especially if you come in contact with women.


[1]
Eur J Cancer. 1992;28(2-3):415-20.


An endocrine and pharmacokinetic study of four oral doses of formestane in postmenopausal breast cancer patients.


Dowsett M, Mehta A, King N, Smith IE, Powles TJ, Stein RC, Coombes RC.




Source


Department of Academic Biochemistry, Royal Marsden Hospital, London, U.K.




Abstract


43 postmenopausal breast cancer patients were treated orally with the aromatase inhibitor formestane (4-hydroxyandrostenedione) at daily doses of 62.5, 125, 250 or 500 mg for 4 weeks followed by 250 mg daily for a further 4 weeks. For some patients, 62.5 mg did not suppress serum oestradiol levels maximally. The doses of 250 and 500 mg did not differ in their effectiveness. Oestrone levels were suppressed by all doses of formestane but no consistent changes of aldosterone, cortisol or 17-hydroxyprogesterone occurred. Serum levels of sex hormone binding globulin fell by about 15% during treatment with 250 mg formestane reflecting its minor androgenic activity. The maximum concentration and area under the curve of serum formestane levels after the first dose varied in an approximately linear manner with dose. It is concluded that formestane is an effective, specific suppressant of oestradiol levels via the oral route requiring no more than 250 mg to be given daily.




PMID: 1591054 [PubMed - indexed for MEDLINE]
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[2]
Dowsett M, Cunningham DC, Stein RC, Evans S, Dehennin L,
Hedley A, Coombes RC. Dose-related endocrine effects and
pharmacokinetics of oral and intramuscular
4-hydroxyandrostenedione in postmenopausal breast
cancer patients. Cancer Res 1989;49(5):1306–12.
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[3]
Dowsett M, Lloyd P. Comparison of the pharmacokinetics
and pharmacodynamics of unformulated and formulated
4-hydroxyandrostenedione taken orally by healthy men.
Cancer Chemother Pharmacol 1990;27(1):67–71.
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mw1 said:
Check some of Dinoii's posts at LB and I think you will find data showing quite the opposite;):)
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What posts are you referring too? Seems he agrees with the research I posted:

dinoiii said:
There is generalized oral dosing in particular and it is sufficient if dosed properly (read: nothing as low as LG Sciences Formdarol at ridiculously low numbers, but reality dosing); the transdermal equivalent of which has NOT shown superiority.

IM is more entertaining, though many are unwilling to use it in this fashion.


D_
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dinoiii said:
Hey Solomon...

Heh, you'd be surprised with all the mud-slinging is going on over the other "steroidal" AIs during PCT, et al right now...how much nonsensical information is being presented. I have elected to stay out of that as so many have asked me how 4-OHAD falls in line here as I have discussed it in the past (reminder: I have no vested interest in my statements at all - as opposed to selective parties).

IN any event, keeping this on topic...you don't really see suggestive suppressive stats with 4-OHAD. Male trials are VERY challenging to find - which is obvious - who cares; the ideal would be a female with ER(+) breast cancer, no?

That said, studies have demonstrated that maximum estrogen suppression is achieved with an oral dose of as little as 250mg per day.

BBers will be bbers, of course and have played around...my own clientele in some cases as well. Not per my suggestion, I just followed their blood work.

A subset has run effectively at 500mg (levels of suppression minimally higher than the 250)

A subset has run at 1000mg (and levels did NOT have an appreciable differentiating effect from the 250-500mg).


I would suggest a dose anywhere from 250-500mg per day. I personally have used the high end at 500mg with success during both PCT and out of it with no suppressive effects on serum gonadotropins suggested at all in either scenario! This is still available but very slim opportunities likely. I would say go with the bulk powder (tastes like a$$, so you're going to want to either cap -or- go with the flavoring system for it).


....[/color][/b]



D_
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mw1 said:
Actually no~ I just haven't had time to dig the info for you;)
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I mod LB. I've read every post Dinoiii has made on formestane and pretty much every post he's ever made there. I've also read/reviewed the latest research (probably 10+ studies) on both formestane and 4-hydroxytestosterone which all support it has perfectly fine oral bioavailability.

Would love to see anything you have that says otherwise.
 
Royd The Noyd said:
I mod LB. I've read every post Dinoiii has made on formestane and pretty much every post he's ever made there. I've also read/reviewed the latest research (probably 10+ studies) on both formestane and 4-hydroxytestosterone which all support it has perfectly fine oral bioavailability.

Would love to see anything you have that says otherwise.
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seeing that our Form is D/Ced its not at the top of my priority list:p
who do u go by at LB?
 
BigBlackGuy said:
YOU!!! at PHF too!?
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He's EVERYWHERE! It's kinda creepy... :lol:

Right Hook/Royd does bring good knowledge though, gotta hand it to him on being well read and thought out! Very consistent and up front too.
 
From the top of my head I've read that the 3b enzyme converts 4OHA to 4OHT.

Maybe someone is getting more 4OHT conversion through TD which might be mislabeled as better "anti-estrogenic" effects?
 
chocolatemilk said:
From the top of my head I've read that the 3b enzyme converts 4OHA to 4OHT.

Maybe someone is getting more 4OHT conversion through TD which might be mislabeled as better "anti-estrogenic" effects?
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It's actually a 17b-hsd enzyme. Formestanes chem name is a dione. So just remember that diones uses 17b-hsd to make the testosterones. And diols use 3b-hsd. And the dhea metabolites use both.

Even so the liver is more abundant with 17b-hsd (and gut) than the skin.
Problem with hitting the intestines and liver is still phase 1 and 2 drug metabolizing enzymes.
Still 250 mgs isn't an unreachable dose orally.
 
Royd The Noyd said:
It's actually a 17b-hsd enzyme. Formestanes chem name is a dione. So just remember that diones uses 17b-hsd to make the testosterones. And diols use 3b-hsd. And the dhea metabolites use both.

Even so the liver is more abundant with 17b-hsd (and gut) than the skin.
Problem with hitting the intestines and liver is still phase 1 and 2 drug metabolizing enzymes.
Still 250 mgs isn't an unreachable dose orally.
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Is AMS coming out with an oral Form product? jk lol

Thanks for the information.

On PP's website it says Formestane has poor oral bio-availability estimated at 4%. References are Anabolic Pharmacology and Seth Roberts.
 
chocolatemilk said:
Is AMS coming out with an oral Form product? jk lol

Thanks for the information.

On PP's website it says Formestane has poor oral bio-availability estimated at 4%. References are Anabolic Pharmacology and Seth Roberts.
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That may be true (would like to see what Seth references), but even than 10 mgs might be powerful enough to reduce estrogen.

Pp's self emulsifying drug delivery system is probably better than just downing some powder. It likely increases lymphatic absorption anywhere from 1-10% which should equal a significantly higher biological response.
Formex was probably even better at that mg for mg.

I may have some stuff sent in to test it out with bloodwork (estrone and estradiol).
 
hmm, something to think about. i've never used it orally, if i was going to go with an oral, i'd pick 6-bromo.

I like transdermals though, better or not, well, that is yet to be seen. I think it can be more convient to apply a t/d and let it slowly be absorbed into the system vs getting it all at once.

what is the half life of formestane?
 
why was formestane even DC'd?
 
jbryand101b said:
hmm, something to think about. i've never used it orally, if i was going to go with an oral, i'd pick 6-bromo.

I like transdermals though, better or not, well, that is yet to be seen. I think it can be more convient to apply a t/d and let it slowly be absorbed into the system vs getting it all at once.

what is the half life of formestane?
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I'll double check later, but if I remember correctly pretty similar to oral steroids (4-6 hours).
 
Because you need 250mg-500mg per day vs 500mg form acetate injection once every 2 weeks

So i guess the assumption was injection was better so we need to rub it on our skin since we cant inject supplements.

Oral formestane works, if you take enough. I have never seen a supplement supply enough
 
nattydisaster said:
Because you need 250mg-500mg per day vs 500mg form acetate injection once every 2 weeks

So i guess the assumption was injection was better so we need to rub it on our skin since we cant inject supplements.

Oral formestane works, if you take enough. I have never seen a supplement supply enough
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Yeah that's sort of like research that finds a statistical significance, but realistically very small.

I thought Formex was a good idea. Some of the lymphatic prodrug research with the MCPE ester is fairly promising. I don't think I ever saw any bloodwork on the stuff though.
 
Didn't Formex have a higher conversion rate to 4-hydroxy testosterone, and ended up being pretty suppressive? I recall the rumors, but never saw the "proof". The fact that it was D/C'ed makes me wonder though...
 
Milas said:
Didn't Formex have a higher conversion rate to 4-hydroxy testosterone, and ended up being pretty suppressive? I recall the rumors, but never saw the "proof". The fact that it was D/C'ed makes me wonder though...
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I never followed the product much but if that were true it would indicate the ester was doing its job and increasing lymphatic absorption pretty efficiently.
Meaning a 50 mg Formex dose had a similar biological response as maybe 500mg or a gram of unesterfied formestane. Although that would contradict what dinoiii said about his in house tests (even a gram per day was not suppressive).

It may be possible 50mg of Formex resulted in a biological response greater than even a gram of formestane. It's impossible to know without oral pharmacokinetic research on Formex.
 
Milas said:
Didn't Formex have a higher conversion rate to 4-hydroxy testosterone, and ended up being pretty suppressive? I recall the rumors, but never saw the "proof". The fact that it was D/C'ed makes me wonder though...
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No one ever knew if they had the MCPE at the 4 or 17 position, which would change things drastically
 
Royd The Noyd said:
Bump
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IF i remember correctly...

At 17th position there was a risk that trace 4-OH-T was in the capsule and the molecule would convert to 4-OH-T

So then they said oh wait its on the 4th not the 17th label misprint

At 4th position the 4-OH-T thing was avoided but not sure if a 4-MCPE would provide enough lipophilic to make the product that much better. It likely would not do much of anything.

So they discontinued due to risks

I would ask PA on the matter
 
nattydisaster said:
IF i remember correctly...

At 17th position there was a risk that trace 4-OH-T was in the capsule and the molecule would convert to 4-OH-T

So then they said oh wait its on the 4th not the 17th label misprint

At 4th position the 4-OH-T thing was avoided but not sure if a 4-MCPE would provide enough lipophilic to make the product that much better. It likely would not do much of anything.

So they discontinued due to risks

I would ask PA on the matter
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The ether at the 4th would do 1 of two things


1) Leave more 4-oha available after first pass since the 4-hydroxyl is readily rotated to the alpha or beta orientation and/or converted to the keto after reduction of the 4-double bond
2) Get in the way. (i.e. prolong interaction with the aromatase enzyme or prevent some interaction with the aromatase enzyme if the mcpe isn't readily cleaved)
 
btw right hook, it was found that 4-oha given orally to women had (as expected) less biological activity due to less bioavailability because the free 4-hydroxyl group was readily glucuronidated during first pass (instead of during phase II metabolism like most hydroxyl groups).

end of page 6 - beginning of page 7: Invalid Link Removed


but we still don't know the exact bioavailability given orally so it's not precise.
 
Bry17 said:
btw right hook, it was found that 4-oha given orally to women had (as expected) less biological activity due to less bioavailability because the free 4-hydroxyl group was readily glucuronidated during first pass (instead of during phase II metabolism like most hydroxyl groups).
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in the full text of this study Invalid Link Removed (not in abstract)
 
Bry17 said:
btw right hook, it was found that 4-oha given orally to women had (as expected) less biological activity due to less bioavailability because the free 4-hydroxyl group was readily glucuronidated during first pass (instead of during phase II metabolism like most hydroxyl groups).

end of page 6 - beginning of page 7: Invalid Link Removed


but we still don't know the exact bioavailability given orally so it's not precise.
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I know dawg...see first post:

Royd The Noyd said:
Why is it that people think oral formestane has such poor bioavailability. The below reference [1] finds that in women there is no difference in serum estradiol levels between a 250mg dose and a 500mg dose. Estrone was suppressed by all doses.


It should be noted that men likely require about a 15% higher dose simply because we metabolize (glucoronidation) formestane to a higher degree [2-3].


Is there research I am missing? If not, why mess with transdermals? Especially if you come in contact with women.


[1]


[2]


[3]
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This is getting old, but relevant and supportive that oral dosing is good enough...

[h=1]The effects of oral 4-hydroxyandrostenedione on peripheral aromatisation in post-menopausal breast cancer patients.[/h]Invalid Link Removed, Invalid Link Removed, Invalid Link Removed, Invalid Link Removed, Invalid Link Removed.
[h=3]Source[/h]Section of Medicine, Royal Marsden Hospital, Surrey, UK.

[h=3]Abstract[/h]This study investigated the influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA, formestane), given orally, on peripheral aromatase activity and plasma oestradiol (E2) levels in post-menopausal women with advanced breast cancer. The aim was to establish whether an optimal dose could be identified that had a pharmacological effectiveness comparable with that of parenteral 4OHA. A total of 13 post-menopausal women were studied before treatment and after a minimum of 4 weeks on treatment with one or more of the following doses: 125 mg once daily (od), 125 mg b.i.d. (bd) and 250 mg od. In all, seven aromatase studied were performed at 125 mg od; four, at 125 mg bd; and ten, at 250 mg od. Three patients were studied at all doses. E2 was measured concurrently and was available at all dose increments for seven patients. Given at doses of 125 mg od, 125 mg bd and 250 mg od, treatment with formestane inhibited in vivo aromatisation by 62.3% +/- 9.5%, 70.0% +/- 5.1% and 57.3% +/- 5.3%, respectively (mean +/- SEM). Corresponding values for plasma E2 suppression were 30.7% +/- 6.5%, 43.4% +/- 4.5% and 42.9% +/- 6.7%, respectively. Thus, apart from a somewhat better suppression of plasma E2 levels by the two higher doses as compared with 125 mg od, no significant difference in the degree of aromatase inhibition or plasma E2 suppression was observed. The suppression of E2 by oral 4OHA at 125 mg bd or 250 mg od approaches that achieved by the recommended parenteral schedule of 250 mg fortnightly, but inhibition of aromatase at this dose was substantially inferior. The findings are consistent with a hypothesis that 4OHA given orally may cause substantial plasma oestrogen suppression during part of the day, but neither the od nor the bd regimens investigated in the present study were capable of producing optimal aromatase inhibition.

PMID: 7781147 [PubMed - indexed for MEDLINE]
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It works orally. We know that. It just requires too high of a dose. You could take 250-500mg/day oral or inject 500mg acetate ester once every 2 weeks

Thats why the topical method has been targeted...it is the next best thing to injecting it I suppose
 
oh btw, you can't put an ester/ether on the 17th position of 4-oha. it is a ketone. the only place they could've accurately marketed the ether was at the 4th.
 
this study seems to classify form. in the "low bioavailability" category.

...Formestane (4-hydroxyandrostenedione) was the first selective, steroidal aromatase inhibitor
used in the treat- ment of advanced breast cancer in postmenopausal women [5]. Due to poor
oral bioavailability, however, formestane must be administered by deep intramuscular injection...
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^Invalid Link Removedbut regardless, as was said before, the exact bioav. is unknown afaik, so it is still up for guess. i don't think it's poor enough to be below 10% though, given its ability to suppress estrogen at reasonable doses.
 
Bry17 said:
this study seems to classify form. in the "low bioavailability" category.



^Invalid Link Removedbut regardless, as was said before, the exact bioav. is unknown afaik, so it is still up for guess. i don't think it's poor enough to be below 10% though, given its ability to suppress estrogen at reasonable doses.
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Thx ill look at this one later.
 
nattydisaster said:
It would be a hydroxyl group if it was on the 17 position, hence the reason it would convert to 4-OH-T and was pulled
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I said 4-oha. I didn't say 4-oh-t.


It was pulled because it was 4-oh-t MCPE not 4-oh-a MCPE. 4-oh-a MCPE is impossible unless at the 4th position. i think you know this, but just wanted to make sure folks reading knew that. they pulled it cuz they probably didn't know they were selling 4-oh-t mcpe
 
Bry17 said:
I said 4-oha. I didn't say 4-oh-t.


It was pulled because it was 4-oh-t MCPE not 4-oh-a MCPE. 4-oh-a MCPE is impossible unless at the 4th position. i think you know this, but just wanted to make sure folks reading knew that. they pulled it cuz they probably didn't know they were selling 4-oh-t mcpe
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Vida has pretty good evidence that adding a 17 position MCPE improves oral bioavailability, which probably explains the results people got from it
 
They sorta make it sound bad orally but the suppression is still good imo. No need to kill E2...

Invalid Link Removed 1995;36(3):249-54.
[h=1]The effects of oral 4-hydroxyandrostenedione on peripheral aromatisation in post-menopausal breast cancer patients.[/h]Invalid Link Removed, Invalid Link Removed, Invalid Link Removed, Invalid Link Removed, Invalid Link Removed.
[h=3]Source[/h]Section of Medicine, Royal Marsden Hospital, Surrey, UK.

[h=3]Abstract[/h]This study investigated the influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA, formestane), given orally, on peripheral aromatase activity and plasma oestradiol (E2) levels in post-menopausal women with advanced breast cancer. The aim was to establish whether an optimal dose could be identified that had a pharmacological effectiveness comparable with that of parenteral 4OHA. A total of 13 post-menopausal women were studied before treatment and after a minimum of 4 weeks on treatment with one or more of the following doses: 125 mg once daily (od), 125 mg b.i.d. (bd) and 250 mg od. In all, seven aromatase studied were performed at 125 mg od; four, at 125 mg bd; and ten, at 250 mg od. Three patients were studied at all doses. E2 was measured concurrently and was available at all dose increments for seven patients. Given at doses of 125 mg od, 125 mg bd and 250 mg od, treatment with formestane inhibited in vivo aromatisation by 62.3% +/- 9.5%, 70.0% +/- 5.1% and 57.3% +/- 5.3%, respectively (mean +/- SEM). Corresponding values for plasma E2 suppression were 30.7% +/- 6.5%, 43.4% +/- 4.5% and 42.9% +/- 6.7%, respectively. Thus, apart from a somewhat better suppression of plasma E2 levels by the two higher doses as compared with 125 mg od, no significant difference in the degree of aromatase inhibition or plasma E2 suppression was observed. The suppression of E2 by oral 4OHA at 125 mg bd or 250 mg od approaches that achieved by the recommended parenteral schedule of 250 mg fortnightly, but inhibition of aromatase at this dose was substantially inferior. The findings are consistent with a hypothesis that 4OHA given orally may cause substantial plasma oestrogen suppression during part of the day, but neither the od nor the bd regimens investigated in the present study were capable of producing optimal aromatase inhibition.

PMID: 7781147 [PubMed - indexed for MEDLINE]
 
Definitely reduces E, i wouldnt depent on it while running wet compounds though. Nice as a standalone. Expensive for oral.

The main thing I like about oral use that injectable (transdermal assumed like injectable) didnt show was SHBG reduction
 
nattydisaster said:
Definitely reduces E, i wouldnt depent on it while running wet compounds though. Nice as a standalone. Expensive for oral.

The main thing I like about oral use that injectable (transdermal assumed like injectable) didnt show was SHBG reduction
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Which reference does the shbg comment come from? I'm still waiting for a few full texts on library interloan
 
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