Kathec, AI's metabolize thru 2d6 ,3a4, and other routes. Testing for 2d6 was complete when the AI's were being tested. Knowledge of 3a4 changed in 2011 when a new abnormality in the 3a4  allele's was identified. As in all science, what was true yesterday, may not be true today. Sorry Kathec your doc was wrong

This is from dailymed.nlm I'll bring the link

"Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites."

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?se...

Dailymed.nlm is the web site established by the government---I'll have to say for once they really did something right. The first drug on the list when you use the search mechanism is the original packager of the rdug. The origiinal packager ( first approved by FDA) has to include all trial data and post marketing info. Great web site.

This is the metabolism of Aspirin---Interesting found more than expected b/c I couldn't get the simpe source to C&P

CONCLUSIONS: from article --link below.

The effect of low-dose aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity awaits further confirmation. When low-dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy.

http://www.ncbi.nlm.nih.gov/pubmed/12621391

Can't be to complete and fastidious ---the two don't overlap at 3A4.

For those reading this, we all need to work on understanding the CYP450 system. If a Doc that is highly influential in the NCCN hasn't got a clue about the minimum basics of how the system functions, what can we expect of anyone else. 

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

I have changed the practice of my PCP and Councelor. I know my MO's practice of 7 docs and 2 ARNPS do more genetic testing. The were introduced to it in 2010 after I challenged my doc re: the care of my DH in Jan 2010. The had a full staff seminar in June 2010. What was covered I don't know. 

I haven't revisited the subject with him b/c I'm way beyond treatment---5th year cancerversary Jan23rd ,2014---. I will discuss it with him at next visit. MY genetic testing was done through my PCP . MO is unaware of results. I rec'd the abnormal 3A4 and 3A5 results last week. Hence, my soap boxing this week.

the monograph you provided on aspirin is from 2003.

....and i stand by my doctor. i am just glad that in this day and age, i live in a country where i have an opportunity to be receiving any treatment at all. in some countries, women are really dying of this, horribly, every single day. with no treatment, no testing.... of any kind.

Hi, Kathec-please, aspirin isn't the issue here. 

The drugs I'm concerned about are the chemo-therapeutics. All the AI's go through the 3A4 enzyme path. If there is an abnormality in this path, as intermediate metabolizer, the drug dose should be reduced. The abnormality of 3A4 *1/*22 was identified in 2011. When the research on the AI's was done , this wasn't known. 

All drugs had/have to be re-looked at to see if this newly identified abnormality applies.

Quoting you:"...what sas is basically saying from her research, is drugs must be tested in the lab before trying them on humans.". This has been the standard since the 1930's with refinements in technique and more requirements added over time.

What the article above re:in vitro research defines is that the process in the 80-90's became refined enough to be acceptable. That was important in that time b/c the FDA required that this information be included in each drug monograph. This statement re: the FDA isn't in the article. So, at first glance you may perceive the article old. It's value is, it stated in 2000, that the science was ready to comply with the regulatory law passed by the FDA. That the monograph could be trusted by the reader to define the route the drug took. 

Until genetic testing for CYP enzyme paths, laboratory analysis or human analysis through drug trials couldn't be applied universally b/c our genetics weren't known. Trials done now without knowing genetics of the subjects are useless.

Kathec, I know it's hard to think our docs don't know something. Trust between doc and patient is paramount. But they are human. The explosion of information in all of science since 1940's, has been like a steam engine barreling down a track. Your doc is in a position of influence in NCCN. He wouldn't be there if he wasn't knowledgeable about cancer. But he has an achilles heel. His statement was wrong. My doc was wrong, but I realize he's human. My approach is I will teach him. It's happened before. He's open to it. Actually, my docs have to be open to learning from any source. It's part of my criteria for choosing a physician.

Thank you for taking the time to express your opinion, I think it helped to generate a good exchange.

I have a question and it may seem very simple minded. What is a pathway in terms of a pathway that a drug takes? I understand neural pathways, but not pathways in this sense. My second question (also pea-brained)  is what is meant by a 'first pass'? Is this the drugs first attempt at being processed?

Ziggy my dear friend, It's 2:12am----I've been here since early am. Going to see if my melatonin was metabolized. I will check in in am. If you would like something more detailed let me know? Goodnight.

Thanks to my insurance company dumping my onc. Practice I have a new MO.  I've only met her once, but think I'm going to really like her. She seems more open and knowledgeable than the other. And she was in the old practice!

So when I see her again I'll let her know what's being discussed here. Which had me in a strange funk yesterday. Close to tears all day. Was/is it relief, that if I changed to the newer blood thinner, I could do chemo if I had to? That's been a big fear for me. Pi$$ed because MO didn't know and I went through that hell? Gotta go, tears coming

HEY VR almost pm'd you when I posted things two days ago. With your research love an skill, I knew you would add to the discussion. Need to get Kay B here too.

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.

2d6, is one of six major players in the drug metabolism pathways.  Not all drugs pass through  2d6,  25%. One quarter of all drugs is not a small number. Once tested you never have to be retested. Anytime in the future when a drug is used, it's metabolism can be evaluated against your known genetics. 

I was an advocate for testing since 2010, but PCP who was supportive had to work on getting things set up between her an G and insurance. There was no imperative for me to test. July 2013, I was tested the panel was the "2"'s and VKORC1.  The "2"'s all came back normal. VKORC1 was intermediate(abnormal). The "3"s were offered in Sept 2013. I got around to being tested for them this Jan. 2014. I'm here trying to stir things up b/c of the "3"'s abnormal result. 

I've known for many years, I had to start low on drugs, and evaluate closely effect. Now I know why, as 50% are metabolized by the "3"'s. As you have read above, my experience with the AI's and Taxotere could have been different if this had been known.

If you read what I wrote about my experience of manipulating my DH's drugs during his chemo's, the value of knowing all 6 players/enzyme paths would have been invaluable. Without actually testing, I cross referenced all his drugs based on  enzyme pathways listed in monographs information stored in Genelex's database. other sources that I may have used have been forgotten. Many hours of work. I did it b/c his first chemo response was awful. His was not adjuvant. He didn't have the luxury to say I quit. His response to remaining chemo's was much better based on my drug plan. I even manipulated his insulin b/c of observation and my documentation of his blood sugars during chemo and after that first chemo. During and for x number of days after his insulin had to be drastically reduced to the point that no standard dose was indicated. Effectively he was on a sliding scale. TMI or perhaps not enough.

When I was done with the initial chart. The obvious thing to me was that many drugs were "bumping into each other in the 6 pathways. The '3''s were the highest. Now I know that would have been predictable b/c 50% of all drugs take those paths. 

Why would I be so bold as to take the responsibility of determining his drug doses except for chemo drugs. None of the doc's or pharmacists would do it. All were asked. All refused.

Empirically, I will say he had some abnormalities in genetics. Can't be proved, he's dead. If his genetics were known, his drugs would have been prescribed by applying the genetics to known information. In determining his treatment plan for chemo, all drugs would have to be evaluated for drug interaction, looking for complete blocking, inhibition, or inducer(making drug act faster) activity.

I was looking for a particular publication that was just published regarding the above scenario overall, but can't locate it. This link is an other example if the genetics, and known drug activity would have been applied, outcome would have been different. It's about a patient on Tamox and then given Paxil.

http://www.psychiatrictimes.com/depression/medicat...

You have always referenced how your DH has to be monitored closely for drugs that cause horrible to near deadly effects. Now how the genetics would apply to him I don't know. But what if the genetics are the cause or part of the cause of many of the complications from drugs that he has been subjected too? His Main condition is outside the liver, but I know you are a lion when he's admitted to prevent errors. Does this not make sense that we've moved to the next level?

We need to bring the docs to the new level, to protect ourselves from injury. Paintball therapy is no longer acceptable.

. 

Ziggy, glad the simple is good. You're no pea-brain lovey LOL Your questions and  then final analysis are very astute. You always find a way to reduce the complex to the simple. That's not easy. It's tricky to do. So, your input here is much appreciated. I am going to bring your analysis of the last few pages on our home thread here. The comic relief for a moment here would be good to ease the brain.

Spookie---sorry for the tears. You went through hell with your chemo's. If you get the genetics done and they show that your very abnormal response to the medicine could have been avoided, may be you have an actionable case. At the very least you can raise hell. For those reading this Spookie lost all her skin from her chemo. It was incredibly painful. It was amazing she survived her life saving treatment. Spookie, it sounds as if your new MO will be responsive. You are a poster child(adult) for why genetics are necessary.

Drug affects can occur outside the CYP450 system, but unless we test, we can't be sure if it's something that could have been avoided. Otherwise, it's PAINTBALL Therapy. I coined this phrase so long ago, I can't remember. Perhaps 30-40 years ago. Definition: when a  paintball is thrown at a wall it will splatter all over. Drug development even now produces drugs that have not just direct affects, but many side affects that are problematic. The side affects are the splatter. The goal of drug development has been to get the targeted affect to a specific spot with out affecting other body areas. Reduce the splatter. 

Testing reduces the splatter by allowing drugs to act as expected.

Sheila...once you read the above referenced link, here's something interesting to chew on!  With respect to the  "ultra-rapid" Tamoxifen metabolizer breast feeding mother and infant child, I had read about that case several years ago and drew some of my own conclusions with respect to myself.  It appears that the infant died because the mother was taking codeine and because she was an "ultra-rapid" metabolizer, it was assumed that the codeine which also uses the CYP2D6's pathway, was rapidly being broken down into morphine and the child died from a toxic reaction through the mother's breast milk.  When I first read about it, I wondered, since I was an "ultra-rapid" metabolizer, if that explained why I am intolerant to codeine.  When I was given it in the past, I became violently ill.  Could I have grown ill because I was rapidly turning the codeine into morphine?

I really can't get into the whole issue regarding the DH and all the testing that they do on him.  Let's leave it at that.  Way. Too. Complicated.......However, I will say only one thing that is a red herring right now with respect to his illness and genetic testing of various enzymes and pathways.....  When the DH was diagnosed, it was apparent from genetic testing that his body was deficient in an enzyme that helps the body process fatty acids.  Okay.  That's easy enough to understand.  Now here's where it gets muddy.  You can take TWO people, any two people who have the disorder.  They could be siblings or strangers.  Now, you would think that the individual who has LESS of the deficiency in the enzyme would have WORSE symptoms.  Nope!  There are some individuals who have MORE of the enzyme and STILL have WORSE symptoms than some individuals who have LESS of the enzyme.  So the takeaway message RIGHT NOW, that is until more research discovers how these enzymes work,  we are STILL far away from understanding EXACTLY how these enzymes and pathways work and where the understanding of pharmacogenomics works within that setting. Oy.

For a wonderful understanding about the future of medicine, if you haven't read Eric Topol, MD's The Creative Destruction of Medicine, I STRONGLY recommend that his book be read.  He devotes much of the book to pharmacogenomics....

http://www.amazon.com/The-Creative-Destruction-Medicine-Revolution/dp/0465025501

Because of the scheduled Thyroidectomy tomorrow, I'm not sure when I'll be back. Could be a couple of hours. Could be days. When I posted two days ago the counter was 1,033 it's now at 1,524. That's significant for BCO. 

Methinks, for myself to read  VR's links with any serious ability to retain info is going to be impaired. Putting the potential patholgy results at bay has been difficult. The indicators are there. Actually, the discussion here has helped. 

For those viewing the thread, please, read, VR's linked material. Register at YouScript, use dailymed.nlm or PDR, or any other drug site that lists the metabolism and hand chart your drugs.  Learn what you can. Initially, the CYP450 system seems overwhelming. But there only six major drug pathways. Learning six is different than learning dozens. The more you repeat 2D6, 2C9, 2C19, 3A4, 3A5, VKORC1. The more they will become solid in your use  and understanding of them as you read. 

Understanding that each of the 6 can have abnormalities in metabolism is easy at this point. Knowing that the greatest percentages of abnormalities in the population are in the 2's. The 3's are far less common in the general population. The percentages related to abnormalities in the population will change as more people are tested.  Now those population percentages are based on statistical models.

It does get easier to understand Once you have an understanding, then you can decide if you want to push for testing.  Now you depend on your doc to say whether you should be tested. You are taking it on blind faith that they know what they are talking about. Your health and life may depend on your own advocacy sassy

Good luck Sassy!  Hope everything goes smoothly and you are back online soon!