CYP2D6 ability to metabolize tamoxifen and recurrence

Ugh... So I called the lab. They say they can't convert the ng/ml to nmol/l. They suggested I call the manufacturer of Tamoxifen. Called Mayne Pharma - they have no idea either. I finally found the molecular weight of Endoxifen, it's: 373.496, but don't know what to do with that number. Any of you scientists out there that can give me the conversion factor? I'm assuming once you know the molecular weight you'd plug that in to a calculator to get a conversion factor - but I can't find a formula to do that.

Hi Lisey:

With the caveat that this could be COMPLETELY wrong, I provide two calculations for a result of Endoxifen 26.00 ng/mL.

The introduction of Dezentje states (column 2 of the free pdf):

Dezentje (2015), "CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects"

Dezentjé (2015): http://link.springer.com/article/10.1007/s10549-015-3562-5

"In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation."

(Unfortunately, Madlensky is behind a paywall.)

I read the above quote as saying there are 16 nanomoles of endoxifen in one mL of fluid that has a concentration of 5.97 ng/mL. [EDIT: This assumption was incorrect and the units should be nmoles/L per subsequent posts below.]

If my understanding is correct, then to figure out how many nanomoles of endoxifen are in 26 ng/mL, you can divide 26 by 5.97 and then multiply by 16 nM:

26 divided by 5.97 = 4.355

4.355 x 16 nM = 69.68 nM/mL

The above back-of-the-envelope calculation (surprisingly) is relatively close to the result with this on-line calculator:

http://www.endmemo.com/chem/massmolarconcentration.php

The chemical formula and molecular weight (which I think is the Molar mass) of endoxifen can be found on PubChem:

https://pubchem.ncbi.nlm.nih.gov/compound/10090750#section=Top

C25 H27 NO2

373.496 g/mol

Above, when I entered 373.496 and the chemical formula, it changed the Molar Mass to 373.48738.

Below, when I entered 373.496 without the chemical formula, I got the following result:

By the way, for both calculations, I selected units of nmol/mL for Molar Concentration, and hit "calculate". Both calculations yielded a result of 69.6 nmol/mL.

Dezentje also noted that the median endoxifen serum concentration in EMs is 33.7 nM with a range of 7.1 to 87.3 nM:

"Previously, the average endoxifen serum concentration in EMs of 33.7 nM (7.2–87.3) was determined by using the median endoxifen level in the first 586 patients included in the CYPTAM documentation study just before initiating the pharmacokinetics study at that time consisting of 292 EMs [13]."

". . . and the median endoxifen level in EMs without dose escalation (33.7 nM)."

I am not sure why when discussing a serum concentration they dropped the mL, but if they are talking about 33.7 nM/mL, with a maximum of 87.3 nM/mL, then around 69.6 or 69.7 nmol/mL would make sense at least.

BarredOwl

Barred, THANK YOU... that's exactly what we needed. I knew someone with a scientific brain on here could do what it seems the pharmacist, the lab, and the Tamoxifen manufacturer could not. This is extremely helpful. Not just for me, but for others.

Hi Lisey:

I think my units above are messed up. Here is another document that discusses Madlensky:

Barginear (2011): http://onlinelibrary.wiley.com/doi/10.1038/clpt.2011.153/full

Pdf available for free download from ResearchGate here:

https://www.researchgate.net/publication/51626806_Increasing_Tamoxifen_Dose_in_Breast_Cancer_Patients_Based_on_CYP2D6_Genotypes_and_Endoxifen_Levels_Effect_on_Active_Metabolite_Isomers_and_the_Antiestrogenic_Activity_Score

"According to that report, individuals in the lower quintile with endoxifen levels <5.9 ng/ml (15.8 nmol/l) . . . "

"As stated above, women with low levels of endoxifen (<5.9 ng/ml, or <16 nmol/l) . . "

If the Dezentje reference to "16 nM" (nanomolar) means "16 nmol/L", then my units should have been nmol/L.

Using the calculator with "Molar Concentration" of "mol/L":

http://www.endmemo.com/chem/massmolarconcentration.php

Then, converting moles per liter to nanomolar (nmol/L):

http://www.convertunits.com/from/moles+per+litre/to/nanomolar

BarredOwl

My endoxifen was 12 ng/mL, which is 46% of LIsey's 26.

46% of Lisey's 69.61 nmol/L is 32.02. When I used BarredOwl's calculators I got almost exactly the same result, so you can estimate your own level from our results without using the calculators if you prefer.

A note on the 30 nmol/L target. They say in that study (posted in this thread more than once), they "did not seek to define an optimal therapeutic endoxifen concentration," and acknowledge that other studies have shown that about half of that may be enough. Based on the research that has been done there is no reason to fixate on the 30 nmol/L number. The honest answer is that they do not know yet, but best evidence to date is that around 15 nmol/L and above may be enough.

"At the time of commencement of the study, there were few data available to indicate a therapeutic level for endoxifen. Hence, for the purposes of evaluating the effect of dose escalation, an empirical approach was taken to define the study target of 30 nmol/L. Since then, two studies have been published that indicate that an endoxifen level of approximately 15 nmol/L may be a critical level for anticancer effect. The Women's Healthy Eating and Living (WHEL) Study of 1,370 patients with ER-positive early breast cancer reported that relapse rates were higher for patients in the lowest quintile of endoxifen levels corresponding to levels < 5.9 ng/mL (or 14.2 nmol/L). More recently, Saladores and colleagues, have shown in 306 premenopausal women on adjuvant tamoxifen that those with low (<14 nmol/L) compared with high (>35 nmol/L) endoxifen concentrations were associated with shorter distant relapse-free survival (19)."

congrats to you solfeo. I'm only 41 and probably have at least a decade more to go. I tolerate tamoxifen perfectly, so as long as I don't get uterine cancer, I want to stay on it. I haven't had a uterine test though, not sure what to look for. I've never had cysts or anything...

I'm doing well.. praying the tamoxifen is working.

Good for you, Solfeo! My estradiol was still super high in January, but I feel ready to test it again as I am having lots of SEs that could either be Tamoxifen (been on it a little over 2 years) or menopause. I would also be happy to be in your shoes. I am resisting getting an ooph, even though my MO is all for it and wants me on Femara. He also believes that Tamoxifen builds resistance after two years, but I think that is mainly based on his experience with Stage IV patients. I wonder what the resistance stats are for early stagers? While I am having a lot of SEs now, I am reluctant to go on something that will increase other health risks, esp. heart disease risks as my family has some issues there, and I already have some unfavorable markers.

I didn't really change anything. I did lose most of the rest of my weight during that time period, which would have had some effect, but not enough to cause such a large reduction. I think it was just my time.

solfeo, glad to hear your estrogen levels are down. if you recall, mine also spiked, for 8 months and i had ovarian cysts! I was considering ooph. but we did one more blood test and ultrasound in Dec. before making the final decision and levels were down in and cysts were shrinking. MO tested again this month and they have stayed down. I will be switching to an AI in a few months. I want to make sure I get a bone scan and lipids tested before I start. I also think the drop was natural - finally going into menopause at 53-54 yo! jojo