CYP2D6 ability to metabolize tamoxifen and recurrence

Thanks for all the warm thoughts. Can you imagine the poor anesthesiologist today. I talk like a magpie after getting versed. I'll be talknig 2d6,2c9, 3a4, intermediate this, 3a5 won't work right. He'll likely push a little more versed to put me out LOL. 

Have fun studying L&H&P's sassy

Sas, just wanted to wish you well. Hope you are well recovered soon!

Maddy read page one there is a letter that i suggested anyone use for discussion with their doc or insurance company. Read it. See if they are words you could use. Perhaps they are words that can help you find your own. Go lightly on the legal action words. Right now you want to convince him to support testing. 

Sounds like Tamox is a better choice for you. If you look at the metabolism section of each drug at dailymed.nlm. you will see that Tamox and Anastr. take different pathways.

Good Luck.

savigigi-Hellloooooooo thanks. Kicking better everyday. Wasn't prepared for the serious swallowing problems----learn sumpin new everyday. Love the effect the new level of thyroid med is having on my whole body. VERY NICE. Guessing under dosed for years and years. So, the thyroid going kafluey enough to have both docs agree it should come out versus medical management was a blessing in disguise.

Were having a bit of discussion on Insomnia thread re:thyroid, if anyone reading wants to either join and or lurk, please, do. 

In the previous discussion, Kathec brought up the age of the Aspirin citation as being 2003. It's a good point to follow up on. The FDA in the 1990's, charged the drug companies to define the enzyme pathways that drugs follow. They only need to do it once for known paths. 

The accepted method of In Vitro analysis is in the abstract on page 2. 

How this will change for all drugs is when a new path is identified, or when an existing path is shown to have a new metabolism effect not previously identified. This occurred in 2011 for 3A4 & 3A5. Drug companies had to retest all their drugs to show how they would be metabolized based on the new information.

Below is a list of the major players 2D6, 2C9, 2C19, 3A4, 3a5, and VKROC1. Please, do not be intimidated by the subcategories. When someone receives their testing results. The information will include one from each category. I've included all the potential ways a drug may be metabolized for each enzyme path. This is for completeness. It is to demonstrate that there are difference metabolism rates and mechanisms for each path. 

The important need to know information: Drugs are metabolized by each persons individual genetics. All below here for our learning is simply to know that different rates and mechanisms exist.

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

2D6-----10

• 2D6 Intermediate Metabolizer
• 2D6 Intermediate or Poor Metabolizer
• 2D6 Normal Metabolizer
• 2D6 Normal or Intermediate Metabolizer
• 2D6 Normal or Ultra Rapid Metabolizer
• 2D6 Poor Metabolizer
• 2D6 Ultra Rapid Metabolizer
• D-23129
• D3
• Daio

2C9-----09

• 2C9 Intermediate Metabolizer
• 2C9 Normal Metabolizer
• 2C9 Poor Metabolizer
• goya
• GW572016
• HCG
• K
• K2
• kaa

2C19---10

• 2C9 Intermediate Metabolizer
• 2C9 Normal Metabolizer
• 2C9 Poor Metabolizer
• goya
• GW572016
• HCG
• K
• K2
• kaa

3A4----3

• 3A4 Intermediate Metabolizer
• 3A4 Normal Metabolizer
• H

3A5----4

• 3A5 Normal Metabolizer
• 3A5 Rapid Metabolizer
• 3A5 Ultra Rapid Metabolizer
• H

VKROC1

• VKORC1 -1639 A/A
• VKORC1 -1639 G/A
• VKORC1 -1639 G/G
• VKORC1 High sensitivity to warfarin
• VKORC1 Intermediate sensitivity to warfarin

• VKORC1 Low sensitivity to warfarin

• Rates and mechanisms of metabolism  are copy and pasted from YouScript web page.

SAS.... Topol devotes a whole chapter to genomics in his book.  While reading it, he explained that there was a genetic test for testing the blood platelet drug Plavix, which is prescribed following cardiac stenting. Since the DH was taking the med, I asked that he be tested and found he was an intermediate metabolizer.  When he was stented,the hospital did NOT regularly test patients.  Nowadays, the test is more common.  However , if a platelet drug is prescribed, I would ask if the test is being done.  Nowadays there are second generation anti -platelet drugs to use instead, so testing is more common now.  Unfortunately it is still NOT included in the standard of care.  Soooo, patients must educate themselves about genomics and insist on pharmaceutical genetic testing.  For the record, the DH is now taking Effient instead of Plavix.

Questions from a PM from kayb

Hi Sheila - I just tried to jump in and got logged out as I tried to post a bunch of questions. ARRGGHHI'm going to try it here, if I can remember some of what i said.

Frist of all - this is a fascinating subject I've paid no attention to before but see that I must. Since the tests are available, it seems nearly criminal to prescribe certain drugs without knowing how a PT will metabolize them. Talk about personalized medicine! What is the current cost of testing?

Please explain this basic thing for me. I'm reading in different places and not sure I fully understand:

1. Inhibition of tamoxifen with an SSRI lowers endoxifen levels thus increasing risk of recurrence, but reducing SEs like hot flashes.

2. A poor metabolizer of tamoxifen will have the drug spill over to other pathways that metabolize the drug less efficiently, causing serum drug levels to rise resulting in more SEs, but still increasing risk of recurrence.

Are these similar? In one case, a person's genetic makeup prevents metabolization while in the other it's drug induced? I think I read that a poor metabolizer might actually do better taking a smaller dose of the drug. Did I get that right? Please help me start to wrap my brain around this. It's such an important subject.

Hi Ladies!

I am an intermediate metabolizer. My Dr suggested 40mg daily Tamoxifen for 5 yrs (or I can forget about the CYP2d6 test and take 20mg) . I can not find any data on how the escalated dose would affect the side effects profile in intermediate metabolizers. Very stressed and worried about making the right decision. Has anyone was suggested to double the dose?

Hey kayb, I'm with you. Do you think I'm correct in thinking that her doc thinks she should have twice the drug versus half the drug. 

I would feel comfortable with getting the advise of the genelex pharmacist. I know my doc and counselor are always "couseling" with genelexs pharmacist to get the doses right and suggesting alternatives when things are inhibiting or inducing. I shouldn't use slang in the learning phase. But when I was trying to do this by hand with making a chart of all drugs DH was on. The phrase I used was that the certain drugs were all "bumping into each other". 

VR, re-read your post again. Some new thoughts. Plavix if given to your DH as an intermediate metabolizer at usual range dose would be a relative over dose. Add to that there is no reversal agent for Plavix. ThankGod you are the researcher you are, but you have always been his advocate. 

I plugged both Plavix and Effient into my profile. They'd have a hell of a time trying to find something for me b/c of drug to drug interaction and my  '3's abnormalities. But what's so cool is I can advocate for myself, by signing on and plugging them in to my profile. And going right to the right boxes that describe what the problem is and how it can be fixed --cool.

kayb, can you post a sourse of this info, please?

My test was done via my MO, it was a blood test. I will ask the copy of the results. The doc explained it to me in a simple words saying I have 1 good allyl and 1 defective allyl, that makes me Intermediate metabolizer, meaning 20mg Tamox may not be enough for me... so if I believe in this test I should take 40mg  ( the benefit will be the same as 20 mg in a person with normal Cyp2d6)

kayb, In order to speak to "yourscript" pharmacist, do I need to have the test done through their lab? 

thank you kayb!!!

Kayb thank God for your insatiable curiosity. You've brought here more than I could by a long shot. VR is following on the side lines b/c of Dh's problem. I'm sure she is pleased with what you have brought to the discussion. 

At first it will seem like gooblygook to the new reader. BUT THE CLEAR MESSAGE IS THERE SHOULD BE NO SHOOTING FROM THE HIP. IN GENERAL, DOCTORS ARE AT THE BEGINNING OF THEIR LEARNING ON THIS. They are following guidelines. How are we to know if those writing the guidelines are absolutely clear on the genetics.

Hope, there is a clear answer someplace. I believe your best shot at a clear answer is through Genelex and their YouScript. My subscription is under 25.00$. That's the equivalent of a pizza and a picture of beer. They do nothing , but work the genetics with application to drugs. With the free trial you have access to their pharmacists. But there are 51,000+ drugs listed on dailymed.nlm, who can keep up with that. 

I don't know if you've read all the posts here. I recently found out about my'3's abnormality. 3A4 IM. My dose of taxotere should have been reduced. My reaction to my first chemo of Cytoxan and Taxotere (April 2009) almost killed me. In finding genelex in 2010, without knowing my genetics, I deduced that Taxotere was the likely culprit. The genetics on the '3's was done this Jan, 2014. It confirmed that I was right. That's why I restarted this discussion. I DON'T WANT ANYONE TO HAVE TO GO THROUGH PAINTBALL THERAPY.  

I went back to page 1 of this thread---below is a combo of what I wrote last year Dec12, 2012, with revisions I've made today.

Insurance companies have progressively come on board as to paying for testing. Reason: economics versus care for the insured. The testing allows drug prescribers to avoid drugs that can't work b/c the pathway is absent, slow, too fast, or interacting with meds the patient already on. Thus, avoiding a drug with no chance of working or complications created by a drug interaction that could have been avoided. The spectrum of considerations of this subject are HUGE.

*Medicare covers testing

*Insurance carriers that don't cover it may be cajoled into covering it with a letter stating 

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

Dear(insert insures name)

I have been recommended the following medicine(insert name) by my Doctor to treat the following (insert disease). The genetic testing will allow my Doctor to forsee the drugs ability to work in my body and or prevent forseeable complications. 

By taking medicines without knowing the available genetic metabolism, is more costly to you the insurer because you will be paying for the drug(s) as part of my coverage. Also, the potential cost of treating an avoidable complication is an economic benefit that offsets the relative small cost of testing. 

Additionally, I have been tested for 2D6 and have an abnormal metabolism at that enzyme path. Tamoxifen is metabolized through two other paths. 3A4 is included in the panel that I am requesting. If I am shown to be abnormal through that enzyme path, taking Tamoxifen could be deleterious to my health. If you do not respond to covering this panel of tests puts me at risk for serious harm to my body. This letter gives you notice that as of a result of inaction upon your part to a reasonable request, I may incur harm.

Since, I have already been tested for 2D6 test, I am requesting is 2C9, 2C19, 3A4, 3A5, 1A2(if available), and Vkroc1. I would like the test to be run through a company that offers direct pharmacist support to my physician treating me, as the area of CYP management is a complex subject. Only one company offers that link from genetic to drug application. If you can locate another company that offers this equivalent level of care, that would be acceptable to me. 

CYP knowledge is not new, it has been a requirement of FDA to be included in all drug monographs since late 1999. The testing for genetic abnormalities has been available for several years. This is beyond anything that could be described as experimental., 

Sincerely, Hope 70

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This type of letter, also, puts the insurers on notice that if there is an untoward outcome that can be shown that is related to these pathways, there may be a legal recourse for patients.  But you need to get it in writing and sent off. Contact the patient advocate of the insurance company that you are dealing with. They all have them. Ask what else you can do to get the tests covered.

YOhOO, worked on the letter long enough I think it should fly without much modification. All opinions are appreciated.