Sas- I don't know what I am. I just try to be careful and take the tamoxifen by itself and leave a decent window of time before and after any other drug (aspirin) or suppplements.

I do not have a background in biology, chemistry, or medical stuff. Is there such a thing as "Genetics for Dummies"? (seriously, let me know)

Here is some remedial stuff for folks like me just learning this all:

How could one explain phenotype and genotype in layman terms?

This is from memory so don't take it as gospel. I believe tamoxifen is always metabolizing. It has a half-life of about a week and if you take it every day it builds up in your system over a period of months to its steady-state concentration. Endoxifen (active metabolite of tamoxifen that does most of the work) has a longer half-life - if I remember correctly, around 2 weeks. I also take other drugs and supplements separately from the tamoxifen to prevent absorption issues, but I don't think you can totally separate their action.

A question was asked as to how long a drug works. In retrieving information to define this, I looked for a simple answer. Below is the simple answer. Remember you only have to learn it once and they're isn't a test. Your goal should be to have a working understanding for YOU. Between the two sources it does explain why docs tell you to take drugs the way they do. Really! Honest..........Well, Mavehlous, I was able to keep it simple. What is bolded is the need to know info about your drug. I've left the remainder of the info to enhance your learning

To answer this question we need to know two things:1. onset and 2. half life. Onset is cut and dried. Half life is a little more complicated

Onset of Action : The time between the administration of a medication or other form of treatment and the first evidence of its effect.(web dictionary)

Half Life :"Mathematically and biologically, it takes four half life's for a medication to reach steady state, or put another way, a consistent level in the body. For a medication that has a 4 hour half life, it will take 4 doses every four hours to reach the correct level. For this reason, sometimes clinicians advise "to take two the first time", which reduces the amount of time before reaching a steady state.

Also, when a medication has to be stopped, it is often desirable to reduce it over time, instead of stopping it all at once. This may reduce the uncomfortable effects of stopping it. Examples include:

• Narcotic addiction: stopping the narcotics all at once may bring on serious and severe side effects, whereas reducing them a little at a time is more tolerable and comfortable.
• Paxil (paroxetine), like SSRIs generally, is a difficult medication to stop all at once, and should be tapered over time
• Prednisone, and other steroids, may need to be tapered for a different reason...their presence in the body will allow the adrenal glands to "go on vacation", and stopping them suddenly after several days may cause serious problems, whereas slowing them down will allow the adrenal glands to "recover" from the vacation.

Some medical conditions will either shorten or prolong the half life of a medication, which is important for the clinician to consider, to avoid over or under dosing.

• Kidney disease will reduce the excretion of medications that are primarily eliminated through the kidney, allowing it to increase in the blood. This is predictable and should be taken into consideration by the clinician
• Certain medications interfere with the metabolism of other medications, either by speeding up, or slowing down, the metabolism. The clinician has the information to know what does what to what, to avoid this problem.
• Certain foods can interfere with metabolism of medication. Grapefruit and grapefruit juice can cause problems with this, and the clinician may tell one to avoid this food".

https://en.wikibooks.org/wiki/What_You_Should_Know_About_Medicines/Half_life,_or_how_often_to_take_it

To apply the above definition to actual drug use: "a drug with a half life of 4 hours being eliminated in the following way:

8:00 AM Amount of drug in body initially = 100%

12:00 noon Amount remaining in body after 4 hours = 50% (50% has been eliminated)

4:00 PM Amount remaining in body after 8 hours = 25% (~75% eliminated)

8:00 PM Amount remaining in body after 12 hours = 12.5% (~87.5% eliminated)

12:00 midnight Amount remaining in body after 16 hours = 6.25% (~93.75% eliminated)

After each increment of 4 hours the drug is reduced by half or 50%. This process continues until the entire dose is eliminated. This only works as long as the person does not take another dose of the medication. For instance, if the person takes a dose at 8:00 and the medication has a half life of 4 hours and takes another dose in 4 hours and continues to do this every 4 hours then this is what the half life would look like:

8:00 AM – Amount in the body initially 100%

12:00 noon – Amount remaining after 4 hours 50% (Patient takes a 2nd dose, now the medication in the body is actually 150%

4:00 PM – Amount remaining after 8 hours would now be 75% (Patient takes a 3rd dose, now the medication in the body is 175%)

8:00 PM - Amount remaining in body after 12 hours 87.5% Patient takes a 4th dose, now the medication in the body is 187.5%) "

http://instructor.mstc.edu/instructor/csebasti/Pharmacology/Medication%20Half%20Life.pdf

Hey Sas! Still looking for the copies of the testing my SIL had done by a different lab. I'll post it here when I find it. The other lab offers much more detailed testing. I am thinking I might create a type of flow chart for my personal use to map out all my meds . That way I'll have everything in front of me and will be able to reference for future meds.

Solfeo ~ welcome! You have a good memory.......

From the drugs.com link I posted above:

Tamoxifen Absorption and Distribution

Following a single oral dose of 20 mg Tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of Tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl Tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg Tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67 to 183 ng/mL) for Tamoxifen and 336 ng/mL (range 148 to 654 ng/mL) for N-desmethyl Tamoxifen. The average steady-state plasma concentrations of Tamoxifen and N-desmethyl Tamoxifen after administration of 20 mg Tamoxifen once daily for 3 months are 122 ng/mL (range 71 to 183 ng/mL) and 353 ng/mL (range 152 to 706 ng/mL), respectively. After initiation of therapy, steady-state concentrations for Tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl Tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg Tamoxifen citrate tablets given twice a day vs. a 20 mg Tamoxifen citrate tablet given once daily, the 20 mg Tamoxifen citrate tablet was bioequivalent to the 10 mg Tamoxifen citrate tablets.

Sas ~ we posted at the same time I had planned on playing scientist today but FFH just called from work to entice me with an offer of dinner at my fave pizzeria and a trip to a STORE! (sigh) I don't get out much.....

BBL

I have made it my life's work to decipher all of the CYP450 enzyme effects on tamoxifen and avoid interference by other substances. Since I didn't have chemo or radiation I really need the tamoxifen to work. It took me a good month of reading to understand what all of the letters and numbers mean, and how they affect tamoxifen metabolism. I want the genetic test but my MO wouldn't do it because it's not standard. She's retiring and I'm changing MOs so I might be able to get it next month. Not sure if the insurance will cover it though.

Tamoxifen is a prodrug, which basically means it's the active metabolites that do the heavy lifting, as has been discussed here. One thing that is encouraging is that I was given tramadol for pain after my BMX, which worked well the few times I took it. Tramadol is also a prodrug primarily metabolized into its active metabolites by CYP2D6 (codeine is another). So the good news is that if tramadol and codeine work for you, then you are also metabolizing the tamoxifen (but you do need to be careful about taking other CYP2D6 substrates with tamoxifen, because you want to leave the CYP2D6 available for the tamoxifen). Occasional interference shouldn't be a problem because of tam's long half-life, but you don't want to take anything on a regular basis that interferes. It's not just other drugs, either. There are plenty of supplements that are substrates and/or inhibitors of CYP2D6, much to my dismay because I love my supplements. Faster metabolizers can obviously tolerate more interference than slower metabolizers. There are other CYP450s that have a lesser effect, so I'm careful about those too, especially CYP3A4.

I'm doing great, Sassy, thanks for asking! Healthier than I was before the damn cancer. One additional thing I would like to point out about tamoxifen metabolism, is that the half-life is probably going to vary between individuals depending on CYP450 status. 1 week for tamoxifen and 2 weeks for endoxifen would be the average.

Hi again, sassy. Yes, I have read the whole thread and followed it for awhile. Just didn't have anything to add until today. I think your explanation of half-life was good and will be useful to others. Using myself as a typical example of someone who has to work very hard to understand the science I think it would have helped if I read it before I understood any of this. Beyond the basics though, tamoxifen metabolism is more difficult to understand as a prodrug that has to be broken down into its active form to work. Doctors understand the pharmacology if they know about it, but they often are not willing to investigate. Then there are the treatment guidelines to contend with, which are still recommending against routine CYP2D6 testing because of the earlier conflicting studies. I could go on forever about this - for instance, Mayo Clinic found that the studies that show no correlation between CYP2D6 genotype and the effectiveness of tamoxifen were flawed in various ways. The current treatment guidelines are the main reason MOs are not very interested and won't want to run the test.

Statement from NCCN on the subject:

"The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature. Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen. However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects. A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes. Given the limited and conflicting evidence at this time, the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines."

Not because it's not relevant, but because the evidence conflicts. I have read as many studies as I could find, and I totally agree that it is way more important than is officially recognized at this time. I probably go overboard with the caution but I also agree the significance will be proven in time. And even if it isn't, better safe than sorry. If tamoxifen fails me - and it still could - it won't be anything I did to interfere with it.

I think it's been posted before but I'll do it again because a lot of people don't have time to read a long thread like this all the way through. Here's the Mayo Clinic article that questions the validity of the studies that found no correlation (after the first study that was done did find a connection to genotype). Mayo Clinic: Genotyping Errors Plague CYP2D6 Testing for Tamoxifen Therapy. Part of the problem was that the Big 1-98 and ATAC studies looked at the genetics of the cancers and not the person. They can be different, but it is the body that is metabolizing the tamoxifen, not the tumor. I don't have time to re-read it right now, so that oversimplification is from memory, and no one should trust my memory after 6 months on tamoxifen. Anyone who wants a better understanding of what is going on here should read for themselves. There were other issues too, like not taking medications that inhibit CYP2D6 into consideration.

And let's not forget Paxil. Everyone who takes tamoxifen is warned not to take Paxil, precisely because of its strong CYP2D6 inhibition. This problem was discovered when it was noticed that women who took Paxil concurrently with tamoxifen were having higher rates of recurrence and death. Taking it 25% of the time they also took tamoxifen meant a 24% higher risk of death. 50% of the time was associated with a 54% increase, and combining them 75% of the time raised the risk of death 91%. So it matters how long the interference occurs, which is where I got the idea that it's probably OK to occasionally or inadvertently impede tamoxifen metabolism, but not on a regular basis. To be clear, that's just my opinion.

The point is, if CYP2D6 inhibitors are clearly contraindicated, then why is it such a big leap to believe that the original study (sorry I don't have a link right now) - the one that found time to disease recurrence was shortened in poor metabolizers - was the correct one? It makes no sense at all. There are so many areas of the treatment guidelines that are like that. It's like they are prohibited from using common sense! Thank goodness some doctors do, but mine goes strictly by the book.

sas,solfeo,barredowl,shepkitty - thank you for all of the great info. I have a lot of read up on. For those of you who had your metabolism checked - what is it / where/ who/ how much did it cost? I wish I had some codine around to see if it works on me....can't remember! I don't mind taking tamox and suffering the side effects if there is a very good chance that it is helping me. but this not knowing is crazy. jo

I understand their reasoning, I just don't think it's good reasoning when it is probably allowing a lot of women to fall through the cracks. Even I use the word "probably" a lot when discussing this stuff, because I get that no one knows. Tamoxifen fails a good percentage of the time, and when it comes to my life I want to be doing everything I can to make sure that doesn't happen to me. It's not like recurrence is just a blip in the road - it's a freaking death sentence. Besides ego, lack of understanding and group-think mentality, cost is another piece of the puzzle. It costs the system nothing to prescribe a different antidepressant for better safe than sorry reasons, but genetic testing is expensive. They can't justify the costs of testing everyone on tamoxifen when genotype hasn't been proven beyond all doubt to be a factor. As an individual who wants to live through this mess, I would rather err on the side of caution, which is why I will pay for the test if the insurance won't cover it. I shouldn't have to fight to get it.

jojo9999 - Keep in mind that what I said about tramadol and codeine was another oversimplification. If they work it would mean you are also metabolizing the tamoxifen, but you still don't know to what extent. It's a good sign but not proof of anything. That's why I still want the test even though I know I respond to tramadol and codeine. I only have my own experience to go by, and there is no way for me to know if they could be working better than they do if I was a more efficient metabolizer.

Sassy, I see my new MO on June 6th, so I'll see how far I can get with him. Sadly, I did find someone who was known for running these tests, but when I called his office I was told he was closing his practice. There is a real shortage of creative medical care where I live.

Interesting find from the Genelex page on Tamoxifen (bolding is mine):

"Recent research has shown that 7-10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their unique genetic make-up. These women have a version of a gene called Cytochrome P450 2D6, which reduces the effectiveness of tamoxifen and increase their chance of breast cancer recurrence. The evidence is so strong that an FDA panel recently recommended that the label of tamoxifen be changed to say that 2D6 poor metabolizers who take tamoxifen have a higher risk for breast cancer recurrence, and that testing is available."

If this is true then how can NCCN and ASCO justify continued disapproval of testing? I will look into this FDA recommendation further over the weekend and report back with what I find. I also think the numbers are higher than 7-10% (I thought closer to 30%) so I'll check into that too.

BarredOwl, you're probably right that it's old info on the Genelex site, and if so I'll make an effort to have it corrected during my dealings with them.

Solfeo, Great plan, A test in hand can't be argued with.

Solfeo and Jojo I suggest contacting Genelex first. They used to do Panels i.e 2D6, 2C9, 2C19, and VKROC1. When 3A4& 3A5 were identified. They had a panel with that included

In laboratory circles, sometimes a panel can be as cheap or cheaper than running a singular study. i.e test needed is a potassium level, it's cheaper to run a basic metabolic profile which includes potassium and the other major electrolytes. An individual potassium would cost more than a basic met profile.

In the early pages I discussed the percentages of abnormalities for each of these listed above. The 2's have greater percentages of abnormalities than the 3's. The cost/ benefit of testing the 2's is greater b/c the likelihood of abnormality is higher. The 3's are so low in the population 5% an 7% respectively, that wide population testing is less on the cost/ benefit ratio. BUTBUT 50% of all drugs take a first or second pass through the 3's. That's big.

There are two considerations that help to define when the 3's are tested. This is my own conclusions based on patient contacts and my own history.

1. history of difficulty with side effects of many drugs from same or different classifications.

2. History of frequently being successful in using medications at lower doses.

These two concepts I haven't searched to see if they have been studied, but they should be. If why I suggest these two patient historical identifiers is clear please, tell me and I will go into further depth.