CYP2D6 ability to metabolize tamoxifen and recurrence

Cypher this is what my page with my genetics looks like. Don't know if this will work. It didn't copy exactly right, but close enough for you to get the idea of what I can learn from it. For some reason when I cut  and paste it's taking arimidex and putting it in with the active metabolite for Valium. Nope, couldn't get it to C&P and look the same as the web page. Since it's a password protected page. I rather not link it. But their's my report of my genetics.

Patient Factors
2C19 Normal Metabolizer, 2C9 Normal Metabolizer, 2D6 Normal Metabolizer, VKORC1 -1639 G/A, 3A5 Rapid Metabolizer, 3A4 Intermediate Metabolizer

Bump

Ah, the hubris of any age, LOL, Anonymity down the drain LOL . I do so like the phrase paintball therapy. I do hope it does enter the lexicon.

Kayb so right the testing for pathways is ahead of the clinical application b/c determination of individual genetics wasn't a criteria for involvement in the research. AND for example the abberration in the 3"s wasn't known until 2011. The fact that the work of 50% of aLL drugs go through these paths is huge for those people that have an abnormality in the 3's. The 2's weren't even fully understood when research on AI's was done. Tamox is so old, CYP was in the toddler phase of understanding

So, 

1. We have docs that are involved with writing Clinical Practice Guidelines i.e NCCN... that have minimal to no understanding of the CYP work

2. We have docs practicing on the direct care level that, also, have minimal to no understanding of CYP work, that will not vary from the NCCN guidelines

3. We have docs that are more willing to abandon a treatment that may be life saving, than go against the NCCN guidelines

4. We have patients that trust that their docs know what they are doing.

"Houston , we have a problem"

Finally remember why, I made up the words Paintball therapy. I used it to describe the prescribing of antibiotics without the benefit of culture and sensitivity testing. It was making me crazy, not remembering why I first used the phrase.

----------------------

Edit:5/14/2014-----came across a term in reading that is already accepted in medical usage for using a drug with out proper testing. I've not heard it before. It does however apply to how drug's are given without testing

The term is "best guess".

I'm an advocate for testing not guessing.

Interesting stuff, Sas. Reading through the last link, I thought the two paragraphs below were illuminating. If I understand correctly, you can not make a blanket assumption on how your body will metabolize various drugs based on knowing whether you are a high or low expressor of CYP2D6. I had thought if you had low functional 2D6 then you would not metabolize enough of ANY drug using that pathway for it to be effective (e.g. tamoxifen), but it looks like for some drugs it creates toxic levels, and for others it keeps the drug inactive. Very complicated.

"The explanations for the various polymorphisms are thought to be complex, but perhaps the most interesting is the high expression of CYP2D6 in many persons of Ethiopian and Saudi Arabian origin. 2D6 is not inducible, so these people have developed a different strategy to cope with the (presumed) high load of toxic alkaloids in their diet - multiple copies of the gene. These CYPs therefore chew up a variety of drugs, making them ineffective - many antidepressants and neuroleptics are an important example. Conversely, prodrugs will be extensively activated - codeine will be turned in vast amounts into morphine!

In contrast, many individuals lack functional 2D6. These subjects will be predisposed to drug toxicity caused by antidepressants or neuroleptics, but will find codeine (and indeed, tramadol) to be inefficacious due to lack of activation! Other drugs that have caused problems in those lacking 2D6 include dexfenfluramine, propafenone, mexiletine, and perhexiline. Perhexiline was in fact withdrawn from the market due to the neuropathy it caused in those 2D6 inactive patients unfortunate enough to be treated with it. Even beta-blocker removal may be impaired (for example, propranolol) in 2D6-deficient people."

This isn't genetics/genomics related, but you never know who may be reading that wouldn't see it someplace else.

Hi, popping in. I was posting with another member. I thought sharing the below information may be helpful to you .

The link www.needymeds.org is to a web site started by a Social Worker and a doc. It is a tricky site to use. The first page leads to a several hundred resource pages. But I think this first page, does not project the wealth that lies beneath. Be patient when following the links within the site. There are sections that are disease and drug specific. The specific page then links to lists of organizations that provide monetary or other types of assistance.

Register first and do the request for assistances form. Reason: the request for assistance form is filed. If you apply to 1 or 20 organizations/companies, the forms don't need to be repeatedly filled out.  The system is designed to pull information from the original form. There may be a few particulars that need to be added to a companies/organizations form.

All the pharmaceutical companies have patient assistance programs. All the drug manufactures are listed there

The other way to reach drug manufactures is 1. call the manufactuer patient assistance number(goolge keywords: drug name and manufacturer, then to webpage>>>patient assistance. Very time consuming.

There is so much more on www.needymeds.org. It took a bit of time to wander through the whole site. I've shared a telephone walk through with many friends and relatives. I even called healthcare facilities to tell them about this link.

For completeness, there are many ways to get financial assistance for whatever you need. There are organizations that will do things for you i.e volunteers that buy groceries, drive, install handrails, build wheelchair ramps.

How to find the info besides from the link above?  FIND the SOCIAL WORKER(SW).  It's there job to know these things   Talk to all of the following 1. cancer center SW,  2.hospital SW, 3. Insurance companies SW, 4. County SW. 5. church outreach leader.

I requested from my insurance carrier, a consult with a SW. That one appointment with the insurance carrier Social Worker, led to grants totaling $10,550. The meeting with the cancer centers SW, led to coverage of neulasta  for $4000.00.

I won't be posting here for awhile. I thought I'd put together my major thoughts re: CYP testing.

Testing if left to the docs won't happen. We have to learn it, to save ourselves

I'm an advocate of testing for the 6 major players, and of any other players in the future that are shown to influence life with chemicals.

The testing is affordable with insurance. Insurance carriers  and docs should be pestered till they test.

I got so caught up in reading again, that I bypassed  statements that I meant to post here. Whew. This is hard stuff, but it's important.

Starting two weeks ago my PCP and I began to alter my drugs. It will be interesting to see if I have less  medication interactions and side effects.

We are looking to reduce drugs that use 3A4 and 3A5. Mine as you know are abnormal.

One drug choice is metoporol (2D6 only) will replace carvedilol/Coreg(many and 3A4). This will be started after  minimum 2 1/2 weeks off Norvasc.

Norvasc  uses 3A4 & 3A5. I am a 3A4- IM, I would need a reduced dose, 3A5--RM I would need an increased dose. Too confusing.  We took the easy way out, drug was deleted b/c of lower extremity edema (now improved). It's class of drugs are nortorious for causing lower leg edema and Norvasc is the worst.

The bottom line is I have a tool to evaluate the medicines going into my body. My hope is that the information explosion on this subject will be better used by all practioners. That testing for enzyme metabolism and using the knowledge to prescribe medicines becomes the common approach.

Taking a break sassy

Sas, I hope you keep posting. I just starting reading this thread and have to read it through from beginning to end. Don't want to miss any information given here. Thank you for your posts!

Oh BakerBaker---- No, I know what I know, and will say I don't know when I don't.  At first read, my reaction to your question was OH MY, over my head

Alteration by the metabolism from normal, alters how the drug is expected to work. The trails were done without knowing each persons metabolism through 2D6 and 3A4. Which I think, makes conclusions drawn in the trials a crapshoot. Hmmm not a proper scientific response, but if you think of it for awhile, you will understand my point. If my observation is valid, then none of the trial info is valid. Wow, that's messed up.

 For those that have their genetics done through Genelex, they have 1.  pharmacy staff that can work through with the doc on what should be done in other than normal. 2. the computer interface of applying the genetics to the specific drug being used is done. 3. computer also does a drug to drug interaction check based on the genetics. They have all bases covered.

No one else in the world has put the three together. This is an important concept for later as I attempt to respond to your 2 specific questions.

You're very specific questions. I'll work through what I can, but a better answer would come from a top flight researcher.

"#1.Tamoxifen is more effective especially for premenopausal patient. If test shows poor metabolizer, should the patient change to another drug?"

I am not the pro, but will say what I can.  

"Tamoxifen is more effective especially for premenopausal patient."  According to the trials and the approval by the FDA for this drug, this part of your question is true.  But as I stated earlier the genetics of the patients studied within the trials was unknown. Based on the fact that actual genetic metabolism is now available, in order to draw any conclusion how a patient responds, the subjects studied would have to be divided into each metabolism group. That's not been done.

Which leads to the second part of question #1 "If test shows poor metabolizer, should the patient change to another drug?". What I can say, is no one can answer that because it hasn't been studied. What can be done with any drug, is the dose can be altered. The unknown is: Is that altered dose effective. It hasn't been studied. Docs/Pharmacists may suggest that this is the way to do it because it seems logical, but it hasn't been studied.

Both your questions are amazingly challenging. I will say again, I'm not the pro. If the scientific method that is used in all clinical trials, is the accepted method determining effectiveness of a drug, your first question shows the vulnerability of the validity of the drug to accomplish what it was approved for by the FDA.

Getting a bit nervous about this long post getting wiped out. Will submit, then work on your second question

Oh kayb, thanks for the study, knew you'd come through.

Bakerbaker yup way above my head, but can read well enough that controversy is all over it. I agree with kay, take this to your doc.

Hopeful What a very sweet thing to say. Greatly appreciated and will be remembered when someone goes for my jugular.

Re: AI's. Dunno is the final answer. It was so late last night trying to read the article that kayb brought. I have contemplated my response to bakerbaker.

She put two questions together that go to the heart of all research in this period. There is an uniqueness in this point in history and there are scattered pieces of thoughts through all the posts on this thread that I will try to bring together.

The research re:metabolism by in vivo(in the body) and invitro (in test tubes) has been going on for decades. The exact date of the beginning of each is irrelevant, but the acceleration of it was around 1950. Then every decade brought us closer to an understanding of how chemicals move through the body,  work before being metabolized or after, how some are not metabolized and excreted unchanged, and understanding how all the multiple chemicals introduced into the body from any route interact. The disciplines that need to be learned to do what that last sentence said are: Anatomy, Physiology, Chemistry of the body,  Chemistry of all chemicals external to the body, Physics, and Genetics.

The Human Genome project of the 1990's set the stage for the intergration of all the subjects above. The uniqueness of our time now, is we are at the advent of application of genetics to all the physical sciences. Prior to this present period science performed experiments, looked at outcomes, and developed conclusions. There was a turning point for how this was done in the late 40's. The steps of the Scientific Method were formalized, so, that all research in the world followed the same approach to whatever subject was studied. Accepted within the method, is that the outcome of a study is repeatable.  Now that we have genetics as a real versus theoretical tool, all future research will change to include the study subjects genetics at the beginning of the study. All study subjects will be grouped together. Only then can outcomes be predictable.

We know much about the major genetics, but new research is being published every day. The knowledge explosion at this time in history is a blessing and a curse. For us here, there are studies before the ability to use the known genetics and studies repeated after where known genetics were used. The article that kayb brought is demonstrating that concept. In reading that article they are saying that there shoud be retractions of studies because different alleles weren't considered. With the finding of the function(how it works) of a new gene, it will be utilized for future research. Then new research comes out and says whoa we've identified  a variations on that gene. An example, of this is 3A4 a one or two new alleles (variation of the gene) were verified in 2011. So, the research 3A4 is all invalid prior to that knowledge, because now there are two to three ways chemicals are metabolized through that path---not one.

Again restating the uniqueness of our time: identifying a gene, identifying how a gene works, and identifying  different copies (allele's) of a gene that changes it work-- how do we apply that knowledge to the patient. This may not happen all at once. Research doesn't stand still. In our case what drug do we use, how much, and how often today may be the standard and tomorrow is not the standard.. That again recognizes the uniqueness of our time.

Just when we think we have the right answer, new info comes along and causes the right answer to be questionable or wrong.

I think I referenced a quote from the editor of major scientific journal. When questioned about how much of what is published in his journal was true. His answer was "None of it", which was shocking to the interviewerer. The editor went on to say effectively 'What we print today, may be old tomorrow"(paraphrase)

Back to AI's. AI's go through primarily 3A4 without going back and doing a relook. There are the three metabolism alleles Im, N, and rapid. . Definitive studies would have to be done on each for an absolute answer to your question. But only 5% of the population have the variant. I'm one. It does suggest that the studies done on AI's have a greater validity rate than studies done on 2D6 b/c the allele variant rate in the population is much higher for 2D6.  2D6 has 5 variants versus 2. The increase in allele variants and the increase percentage of the presence of variants in the population  causes the results to be more questionable.

Hopeful, hope this all made sense sassy

Sas - thanks for your thoughtful reply. I'm looking forward to sitting down and giving it the time it deserves this evening.

In the meantime, should anyone 'go for your jugular,' I've got your neck!

It's the least I can do, Sassy.