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FYI: Tamoxifen Metabolism Not What You Think


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#1 System Admin

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Posted 11 November 2010 - 10:18 AM

I have been wanting to post this for quite a while and never got around to it but I wanted to explain tamoxifen metabolism and how it variable it really is. I have seen a lot of people post that tamoxifen is metabolized by CYP3A4 and that you should take grapefruit juice with it to inhibit its metabolism. This would be a grave mistake as tamoxifen is a classic pro-drug in the sense that its main effects are elicited from its much stronger metabolites. Tamoxifen itself is both estrogenic and anti-estrogenic depending on the cell line you are referring to, however, the metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyltamoxifen have no agonist activity and has the same binding affinity as E2 itself while tamoxifen has about 30-100x less affinity for the ER than E2. The main point here is that CYP2D6 is actually the enzyme responsible (rate limiting enzyme) for conversion to active metabolites once tamoxifen is converted to N-desmethyl-tamoxifen by 3A4.

Why does this matter?
This matters because CYP2D6 is one of, if not the most, polymorphic CYP enzyme and that means very high variability in the amount of the active metabolite seen from person to person. N-desmethyltamoxifen levels will barely change but endoxifen (4-hydroxy-desmethyltamoxifen) levels are greatly changed. ~26% of caucasians are carriers of at least one *4 allele for the 2D6 gene and homozygotes (those carrying two *4 alleles) actually do not produce a functional enzyme at all. Therefore they have very very low amounts of endoxifen circulating and probably won't benefit much from tamoxifen.

Half Lives
Tamoxifen reaches its highest level after a single dose in about 5 hours but its half life is about 7 days while the endoxifen half life is more around 14 days. Therefore, we could essentially challenge the 4 week standard therapy that people have run for so long and go with something more along the lines of 3 weeks assuming you are a responder and not a poor metabolizer like many people are likely to be. It may be beneficial to choose a compound such as toremifene which is metabolized almost exclusively via 3A4 instead of tamoxifen. Raloxifene is another alternative which is glucoronidated.

Interactions
People need to be aware of what can cause what is called phenocopying. Phenocopying is essentially when a drug forces you to mimic a certain phenotype. In this instance if you are on certain SSRI's or SNRI's such as: Paroxetine, fluoxetine, fluvoxamine, bupropion, and duloxetine you should avoid tamoxifen as they are moderately strong 2D6 inhibitors. Better alternatives as far as less 2D6 inhibition goes are sertraline, citalopram, venlafaxine, and escitalopram although you should never change your SSRI/SNRI to accomodate tamoxifen usage. Just use a different SERM.

Happy PCT'ing :ipitythefool:


LMD
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#2 Marky311

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Posted 25 December 2010 - 12:00 AM

i've been on paxil (30mgs) for about 5 years. After reading this it's obvious i shouldn't use nolva. so i guess clomid it is...? anyone else avoid nolva because of an SSRI they are taking, or any medication for that matter? or has anyone used nolva while taking an SSRI, and how did everything turn out?

#3 SteroidalGazelle

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Posted 29 December 2010 - 03:40 AM

Why isnt there more talk about this topic .... very interesting :thefuk:

#4 RIPO1977

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Posted 29 December 2010 - 11:33 AM

WIKIPEDIA



Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen)[23] which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.[24]
Tamoxifen binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as co-repressors to stop genes being switched on by estrogen. Some of these proteins include NCoR and SMRT.[25] Tamoxifen function can be regulated by a number of different variables including growth factors.[26] Tamoxifen needs to block growth factor proteins such as ErbB2/HER2[27] because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.[28] Tamoxifen seems to require a protein PAX2 for its full anticancer effect.[27][29] In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.[27][30]

WIKIPEDIA
CYP2D6
Cytochrome P450 2D6 (CYP2D6), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds. While CYP2D6 is involved in the oxidation of a wide range of substrates of all the CYPs, there is considerable variability in its expression in the liver. The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1. Alternatively splice
CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism.

CYP3A4
CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs which are used today, including acetaminophen, codeine, ciclosporin, diazepam and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[3] Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins being toxicated into their toxic forms (for examples - see table below).

Edited by RIPO1977, 29 December 2010 - 11:55 AM.

you need a SERM, you idiots

#5 samscar

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Posted 05 January 2011 - 01:28 AM

I take strattera, its an NRI. Here is some info I found, is it ok to take nolva with this?


CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see ADVERSE REACTIONS).

CYP2D6 inhibitors —

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, e. g., paroxetine, fluoxetine, and quinidine (see DOSAGE AND ADMINISTRATION). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6-to 8-fold and Css, max is about 3-to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.

#6 blmcgee81

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Posted 13 January 2011 - 05:47 PM

I take strattera, its an NRI. Here is some info I found, is it ok to take nolva with this?


CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see ADVERSE REACTIONS).

CYP2D6 inhibitors —

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, e. g., paroxetine, fluoxetine, and quinidine (see DOSAGE AND ADMINISTRATION). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6-to 8-fold and Css, max is about 3-to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.



BUMP curious about this also a buddy just asked me about this and I could not find any research on it's use with nolva only the anti-depressants.

#7 System Admin

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Posted 17 February 2011 - 09:55 AM

BUMP curious about this also a buddy just asked me about this and I could not find any research on it's use with nolva only the anti-depressants.


Personally I wouldn't but if you do then you will need to increase your dose of tamoxifen. The problem with this is you have no idea what your polymorphism is so if you are an ultra rapid metabolizer you wouldn't need to do anything if you are normal metabolizer then you would need to. Increasing dose will also increase side effects. Since tamoxifen is most active (by a considerable amount) in its metabolites, you would be losing a lot of potency taking any 2D6 inhibitor with this.
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#8 xikar

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Posted 05 April 2011 - 03:01 PM

I have been wanting to post this for quite a while and never got around to it but I wanted to explain tamoxifen metabolism and how it variable it really is. I have seen a lot of people post that tamoxifen is metabolized by CYP3A4 and that you should take grapefruit juice with it to inhibit its metabolism. This would be a grave mistake as tamoxifen is a classic pro-drug in the sense that its main effects are elicited from its much stronger metabolites. Tamoxifen itself is both estrogenic and anti-estrogenic depending on the cell line you are referring to, however, the metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyltamoxifen have no agonist activity and has the same binding affinity as E2 itself while tamoxifen has about 30-100x less affinity for the ER than E2. The main point here is that CYP2D6 is actually the enzyme responsible (rate limiting enzyme) for conversion to active metabolites once tamoxifen is converted to N-desmethyl-tamoxifen by 3A4.

Why does this matter?
This matters because CYP2D6 is one of, if not the most, polymorphic CYP enzyme and that means very high variability in the amount of the active metabolite seen from person to person. N-desmethyltamoxifen levels will barely change but endoxifen (4-hydroxy-desmethyltamoxifen) levels are greatly changed. ~26% of caucasians are carriers of at least one *4 allele for the 2D6 gene and homozygotes (those carrying two *4 alleles) actually do not produce a functional enzyme at all. Therefore they have very very low amounts of endoxifen circulating and probably won't benefit much from tamoxifen.

Half Lives
Tamoxifen reaches its highest level after a single dose in about 5 hours but its half life is about 7 days while the endoxifen half life is more around 14 days. Therefore, we could essentially challenge the 4 week standard therapy that people have run for so long and go with something more along the lines of 3 weeks assuming you are a responder and not a poor metabolizer like many people are likely to be. It may be beneficial to choose a compound such as toremifene which is metabolized almost exclusively via 3A4 instead of tamoxifen. Raloxifene is another alternative which is glucoronidated.

Interactions
People need to be aware of what can cause what is called phenocopying. Phenocopying is essentially when a drug forces you to mimic a certain phenotype. In this instance if you are on certain SSRI's or SNRI's such as: Paroxetine, fluoxetine, fluvoxamine, bupropion, and duloxetine you should avoid tamoxifen as they are moderately strong 2D6 inhibitors. Better alternatives as far as less 2D6 inhibition goes are sertraline, citalopram, venlafaxine, and escitalopram although you should never change your SSRI/SNRI to accomodate tamoxifen usage. Just use a different SERM.

Happy PCT'ing :ipitythefool:


LMD


Solid info! I have been researching PCT SERM's as much as I can trying to figure out what is best. Ive read a million post by people saying Nolva (Tamoxifen) is ideal. But the recently I have been seeing more and more posts about Toremifene. Am I safe to assume it's a better PCT choice? I will be running my first H-Drol cycle in the fall and I just want to have the best PCT I can. Im was torn between clomid or Nolva, and now Torem is in the mix...LOL. Decisions Decisions!

#9 liquidlava11

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Posted 12 April 2011 - 12:15 AM

Excellent info.. Alot of supps nowadays have bioperine in it. A potent inhibitor. More people should know about these interactions. Inhibitors are only good to potentiate opiates!!

#10 liquidlava11

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Posted 01 May 2011 - 08:22 PM

I take strattera, its an NRI. Here is some info I found, is it ok to take nolva with this?


CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see ADVERSE REACTIONS).

CYP2D6 inhibitors —

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, e. g., paroxetine, fluoxetine, and quinidine (see DOSAGE AND ADMINISTRATION). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6-to 8-fold and Css, max is about 3-to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.


Basically this means that a cyp2d6 inhibitor will increase levels of strattera in your blood. Strattera is not an inhibitor but is metabolized by cyp2d6. Tamoxifen is not an inhibitor just its metabolism is effected by inhibitors. So yes it is okay to take with tamoxifen. Wellbutrin for example is an inhibitor so it would cause issues with tamoxifen and strattera.
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#11 liquidlava11

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Posted 01 May 2011 - 08:24 PM

Excellent info.. Alot of supps nowadays have bioperine in it. A potent inhibitor. More people should know about these interactions. Inhibitors are only good to potentiate opiates!!


Correction....bioperine is an inducer not inhibitor. So in theory it should enhance tamoxifen's absorbtion.

#12 liquidlava11

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Posted 03 May 2011 - 07:54 PM

^Bioperine - cyp3d4 inhibitor - cyp2d6 inducer

Taking bioperine with tamoxifen will increase its absorbtion. So if you are on antidepressants or other drugs that inhibit cyp2d6 then you could take tamoxifen with bioperine to induce the cyp2d6 enzyme.

Edited by liquidlava11, 03 May 2011 - 07:58 PM.


#13 Happy234

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Posted 03 May 2011 - 08:17 PM

Excellent info.. Alot of supps nowadays have bioperine in it. A potent inhibitor. More people should know about these interactions. Inhibitors are only good to potentiate opiates!!


Correction....bioperine is an inducer not inhibitor. So in theory it should enhance tamoxifen's absorbtion.


^Bioperine - cyp3d4 inhibitor - cyp2d6 inducer

Taking bioperine with tamoxifen will increase its absorbtion. So if you are on antidepressants or other drugs that inhibit cyp2d6 then you could take tamoxifen with bioperine to induce the cyp2d6 enzyme.


Ive used bioperine on nolva. I use it almost year round , its in a resveratrol supplement I use.

I think I may be switching over for clomid for quite some time, think i like it better than nolva.

#14 YourMaker

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Posted 29 August 2011 - 10:20 PM

I have been wanting to post this for quite a while and never got around to it but I wanted to explain tamoxifen metabolism and how it variable it really is. I have seen a lot of people post that tamoxifen is metabolized by CYP3A4 and that you should take grapefruit juice with it to inhibit its metabolism. This would be a grave mistake as tamoxifen is a classic pro-drug in the sense that its main effects are elicited from its much stronger metabolites. Tamoxifen itself is both estrogenic and anti-estrogenic depending on the cell line you are referring to, however, the metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyltamoxifen have no agonist activity and has the same binding affinity as E2 itself while tamoxifen has about 30-100x less affinity for the ER than E2. The main point here is that CYP2D6 is actually the enzyme responsible (rate limiting enzyme) for conversion to active metabolites once tamoxifen is converted to N-desmethyl-tamoxifen by 3A4.

Why does this matter?
This matters because CYP2D6 is one of, if not the most, polymorphic CYP enzyme and that means very high variability in the amount of the active metabolite seen from person to person. N-desmethyltamoxifen levels will barely change but endoxifen (4-hydroxy-desmethyltamoxifen) levels are greatly changed. ~26% of caucasians are carriers of at least one *4 allele for the 2D6 gene and homozygotes (those carrying two *4 alleles) actually do not produce a functional enzyme at all. Therefore they have very very low amounts of endoxifen circulating and probably won't benefit much from tamoxifen.

Half Lives
Tamoxifen reaches its highest level after a single dose in about 5 hours but its half life is about 7 days while the endoxifen half life is more around 14 days. Therefore, we could essentially challenge the 4 week standard therapy that people have run for so long and go with something more along the lines of 3 weeks assuming you are a responder and not a poor metabolizer like many people are likely to be. It may be beneficial to choose a compound such as toremifene which is metabolized almost exclusively via 3A4 instead of tamoxifen. Raloxifene is another alternative which is glucoronidated.

Interactions
People need to be aware of what can cause what is called phenocopying. Phenocopying is essentially when a drug forces you to mimic a certain phenotype. In this instance if you are on certain SSRI's or SNRI's such as: Paroxetine, fluoxetine, fluvoxamine, bupropion, and duloxetine you should avoid tamoxifen as they are moderately strong 2D6 inhibitors. Better alternatives as far as less 2D6 inhibition goes are sertraline, citalopram, venlafaxine, and escitalopram although you should never change your SSRI/SNRI to accomodate tamoxifen usage. Just use a different SERM.

Happy PCT'ing :ipitythefool:


LMD


So most of this is over my head but i get the gist. So lets just say i take fluoxetine and i still wanna use nolva in my pct. What will happen??

#15 zebedee

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Posted 30 August 2011 - 12:18 AM

So most of this is over my head but i get the gist. So lets just say i take fluoxetine and i still wanna use nolva in my pct. What will happen??


Your Nolva won't be as effective or maybe even not effective at all as fluoextine is a strong inhibitor of CYP2D6. Go with clomid or torem if you're on fluoxetine.

#16 YourMaker

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Posted 30 August 2011 - 10:53 AM

Your Nolva won't be as effective or maybe even not effective at all as fluoextine is a strong inhibitor of CYP2D6. Go with clomid or torem if you're on fluoxetine.


Thanks for the info.

So I found some torem. It says 60mgs/ml. How do you dose something like that?

#17 Alcatraz

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Posted 30 August 2011 - 11:02 AM

Thanks for the info.

So I found some torem. It says 60mgs/ml. How do you dose something like that?


That usually comes with its own dosing syringe, which is 1cc/1ml. Each ml has 60 mgs of the active ingredient. I've seen some dosing as follows: 120/60/60/30.

I don't know what your doing PCT for, so this dosage may need to be adjusted to fit your cycle.

Edited by Alcatraz, 30 August 2011 - 11:04 AM.
clarification


#18 YourMaker

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Posted 30 August 2011 - 11:33 AM

That usually comes with its own dosing syringe, which is 1cc/1ml. Each ml has 60 mgs of the active ingredient. I've seen some dosing as follows: 120/60/60/30.

I don't know what your doing PCT for, so this dosage may need to be adjusted to fit your cycle.


Hey thanks, man.

I'm trying to put together my first h drol cycle.

#19 umbro

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Posted 10 February 2012 - 03:19 AM

great info, and im digging what i hear about torem. Want to write a breakdown of how that works differences/similarities




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