FYI: Tamoxifen Metabolism Not What You Think

LakeMountD

LakeMountD

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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 :usa:


LMD
 
LakeMountD

LakeMountD

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Thanks, it is a big reason different people are seeing variability in both effect and sides.
 

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