CYP2D6 Enzyme Deficiency

[Nofx5868]

My friend has recently discovered that he either has a CYP2D6 enzyme deficiency, or overactive CYP3A4. He discovered this by experimenting with oxycodone and noticing it didn't effect him the same way it effects everyone else. For example, with no tolerance he can insufflate a 30mg roxycodone and feel no effects. In another case, he can consume a much smaller quantity of oxycodone as part of a cough syrup that also contains DXM, and the effects are much, much more noticible. This is (apparently) because the DXM acts as a CYP3A4 inhibitor, and prevents the drug from being metabolized into the inactive noroxycode substance, while allowing more of it to remain in his system or be metabolized into oxymorphone.

I'm hoping to start a discussion with some of you folks who many be familiar with these enzyme mechanisms, or maybe some others who share a similar disposition. I am still in the process of learning more from various sources on the internet, but I've also got a few unanswered questions that maybe someone can shed some light on.

First, are there any benefits to such a deficiency? Certainly it seems there are some disadvantages, but it also seems equally as likely that there may be some advantages from having abnormal enzyme efficacy. Are there certain drugs that would work better in such a case? My friend is planning to have some lab testing done to determine exactly what is going on with these two enzymes, but those results won't be in for a couple weeks. I have found that there are quite a few substances that inhibit CYP3A4, which, in theory, should help my friend feel the effects of oxycodone more efficiently. Some of the best ones I've found seem to be grapefruit juice and goldenseal. Are there any others anyone can recommend? Also, it seems that inducing the CYP2D6 enzyme would also have positive effects, but there don't seem to be quite as many safe substances that work that way. Finally, is there anything else cool anyone can share about such a condition?

Thanks in advance for any help/discussions, this stuff is really interesting to me and I'd like to learn more...

 

[aced126]

Having a 2D6 deficiency in this case should not be so bad as having a 2D6 deficiency when taking codeine (2D6 metabolises codeine to morphine). Codeine itself is a very weak agonist at mu opioid receptors, and it's pharmacological action is negligible and it only functions as a prodrug. Oxycodone, however, has a very appreciable mu affinity as an agonist and thus having a faulty 2D6 gene won't mean that it won't work. 3A4 upregulation will, however, result in more being N-demethylated to the inactive noroxycodone.

 

[serotonin2A]

CYP deficiencies produce more bad effects than good effects. They increase the effects of acute and chronic exposure to toxins in the environment. For example, the incidence of Parkinson's disease increases. CYP deficiencies may also influence personality because some neurochemicals (eg, neurosteroids) are synthesized by CYP isoforms.

 

[bingey]

Having a 2D6 deficiency in this case should not be so bad as having a 2D6 deficiency when taking codeine (2D6 metabolises codeine to morphine). Codeine itself is a very weak agonist at mu opioid receptors, and it's pharmacological action is negligible and it only functions as a prodrug. Oxycodone, however, has a very appreciable mu affinity as an agonist and thus having a faulty 2D6 gene won't mean that it won't work. 3A4 upregulation will, however, result in more being N-demethylated to the inactive noroxycodone.

this is just not true , morphine only plays a minor role in codeine's effects. Wish I could find some sources for you.

 

[belligerent drunk]

^ I was just about to say the same. It appears that codeine-6-glucuronide is about as important of a player as morphine.

http://onlinelibrary.wiley.com/doi/...ionid=9460534583EF2F6A33500F553F336F5C.f03t04

 

[aced126]

Hmm, that article says codeine-6-G has 60% the analgesic potency of codeine itself. I always thought that codeine was a weak mu agonist (it explains why the people with faulty 2D6 get little analgesia from codeine). Are there any more sources claiming codeine itself plays an important role in its analgesic action?

It is known that carbon 6 is able to accommodate lots of substitutions (including long alkyl chains) yet still fit in the binding pocket, so it does not surprise me that codeine-6-G or morphine-6-G has mu affinity itself. The 3 phenolic group is important however and I if I remember correctly, M-3-G or C-3-G has barely any mu affinity.

 

[belligerent drunk]

That's what bothers me as well. The paper does say that codeine and C-6-G have similar receptor affinities, perhaps their efficacy is different though? Maybe someone could clear this up. I have no idea, but this statement does seem to contradict other data (such as codeine not working for people with faulty 2D6, like you said).

 

[aced126]

this is just not true , morphine only plays a minor role in codeine's effects. Wish I could find some sources for you.

If that is so, what explains the lack of analgesia from codeine in populations of a faulty 2D6 gene?

 

[bingey]

that's a common misconception


From wiki (under pharmakinetics)

Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers

and this (https://en.wikipedia.org/wiki/Codeine-6-glucuronide)

Codeine-6-glucuronide (C6G) is a major active metabolite of codeine and may be responsible for as much as 60% of the analgesic effects of codeine. C6G exhibits decreased immunosuppressive effects compared to codeine.[1] During its metabolism, codeine is conjugated with glucuronic acid by the enzyme UDP-Glucuronosyltransferase-2B7 (UGT2B7) to form codeine-6-glucuronide

 

[aced126]

that's a common misconception


From wiki (under pharmakinetics)
[/I]

and this (https://en.wikipedia.org/wiki/Codeine-6-glucuronide)

The fact is that studies do exist which demonstrate the lack of efficacy of codeine in people who lack 2D6. I think that upon further inspection of the studies which don't find major differences between the 2 sets of populations, we are likely to find other factors at play. For example, there was a study which found that there was no difference in analgesia between 500mg APAP and 500mg/8mg APAP/codeine.

I could only find one research article asserting that C-6-G was mostly responsible for the analgesic effects of codeine. The article doesn't even have a full text available, only an extract.

https://www.ncbi.nlm.nih.gov/pubmed/11092114

Yet there are several articles implying directly or otherwise that codeine analgesia is mainly due to morphine. Here is a recent one: https://www.ncbi.nlm.nih.gov/pubmed/25630571

 

[serotonin2A]

^That article is available in full text:

http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1742-1241

 

[aced126]

^That article is available in full text:

http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1742-1241

What can you comment on the mechanism of action of codeine?

Also, I copied and pasted the article name and searched for it within that journal to no avail.

 

[bingey]

I can not explain the difference in effect profile between oral codeine and oral morphine without codeine-6-glucoronide , codeine is way itchier and has a shorter duration though there is some overlap.

 

[serotonin2A]

What can you comment on the mechanism of action of codeine?

Also, I copied and pasted the article name and searched for it within that journal to no avail.

Sorry, I just realized that online access for that journal does not go back that far...

If you think about the issue logically it is pretty clear that codeine-6-gluconuride (C6G) cannot be the sole mechanism for codeine analgesia. Whatever it is that mediates the analgesia HAS to be more potent than codeine, because there is only incomplete biotransformation to any given metabolite (only 60% of codeine is converted to C6G). So that would mean that C6G would have to be about twice as potent as codeine, which it isn't...

By contrast, the data with morphine is much more consistant. Morphine is 10x stronger, and there is 10% conversion of codeine to morphine. Studies have also shown that CYP2D6 poor metabolizers show a reduced response to codeine.

So I think it is pretty clear that morphine has to play an important role. My guess is that morphine and C6G both contribute. Obviously C6G plays some role because it is active and is generated in large amounts, but it cannot be solely responsible...

 

[bingey]

^
i can agree with that important yes , exclusive no

Pharmacology & Pharmacokinetics
The major effects of codeine are exerted on the central nervous system and the bowel. Like other opiates, its primary effects are a result of binding to opioid receptors in the brain, gut, and other parts of the body. While codeine itself has a weak binding affinity to mu-opioid receptors, 5% to 10% of codeine is converted into morphine, which has a high binding affinity to mu-opioid receptors. The primary metabolites of codeine are morphine and codeine-6-glucuronide. In addition to codeine being converted into morphine in the body, it is also converted into several other active compounds. The approximate distribution of those active compounds is as follows: codeine-6-glucuronide (~70%), norcodeine (~10%), and hydromorphone (~1%).

Conversion of codeine to morphine occurs in the liver via cytochrome P450 enzyme CYP2D6. "CYP3A4 produces norcodeine and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Approximately 6-10% of the Caucasian population, 2% of Asians, and 1% of Arabic have poorly functional CYP2D6 and codeine should be virtually ineffective for analgesia in these patients (Rossi, 2004), although it is speculated that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine and thus these patients should experience some analgesia."1

Some drugs may interfere with the effectiveness of codeine. Certain SSRIs (selective serotonin reuptake inhibitors) are CYP2D6 inhibitors, which consequently reduces the efficacy of codeine. Combining codeine with gluthethimide, a sleeping agent, is said to act as an enzyme-inducer, allowing the body to convert up to 10% of codeine into morphine.2 Other drugs that may increase the effectiveness of codeine include rifampicin, a bactericidal antibiotic, and dexamethasone, a steroid hormone.

http://www.thatspoppycock.com/opiates/codeine/