Trying to understand what it means to be a ultra rapid metabolizer of CYP2D6

[Spadez87]

Hey it took a DNA test last year and I'm trying to find out what drugs will not kill me. I found out I'm an ultra rapid metabolizer of CYP2D6.. I apparently rip through drugs...

So some drugs I need way less such as most opiates?

But say methamphetamine id need more?

For instance I take Codiene and because it's a prodrug my liver turns it into way more morpine then it's supposed to making it easy to od I guess..??

If googled and googled but I don't really understand fully.. I can't ask my doc.

Can someone explain this to me

Anyone else have this tests done and are a ultra rapid?

 

[Libertin]

I'm by no means an expert but I'm interested in the topic and think I can contribute some clarity to the discussion. I haven't been tested but I suspect I am an ultrarapid metaboliser due to my atypical experiences with codeine and dextromethorphan.

I can tell you have some understanding of the topic already but I'd first like to clarify some of the terminology.

CYP2D6 is the name of a gene which encodes an enzyme named 'Cytochrome P450 2D6', this is an enzyme which is involved in metabolising a wide range of drugs. Ultrarapid metabolisers have 2 or more copies of the CYP2D6 gene, therefore have higher Cytochrome P450 2D6 (CYP2D6) enzyme activity. Simply, they break down certain drugs faster than average.

From Wikipedia (lazy yeah I know, I used this source because it helped me to understand):

The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects

A practical example relevant to us; as you know, codeine is a pro-drug to morphine, amongst others. In order for the body to produce morphine from codeine, it has to be converted by the CYP2D6 enzymes, of which you have many. In ultrarapid metabolisers it is converted more rapidly/effectively, leading to greater effective action by the active metabolite morphine (btw codeine also has other active metabolites such as CG6 which is not metabolised by CYP2D6 enzymes).

A contrasting example; if a poor metaboliser (someone deficient in CYP2D6 activity) uses dextromethorphan (DXM), it will not be converted effectively to dextrorphan (DXO); the main metabolite responsible for its pleasant dissociative effects. DXM itself is active and produces some unpleasant effects. So if you take DXM, you want it to be converted to the more pleasant metabolite DXO, in order to feel it's interesting NMDA antagonist properties. The poor metabolisers simply get the DXM exerting its unpleasant effects, lingering in their system for an extended time because they lack the enzymes to inactivate the DXM and metabolise it to DXO.

I was unable to find out much information about the experiences of ultrarapid metabolisers who've used DXM. But you may be interested to know that I have taken 15mg, which I understand to be a very low dose, and experienced auditory hallucinations. Maybe that has something to do with me possibly being an ultrarapid metaboliser - I would be very interested to hear input from others on this topic.

Hope this helps your understanding a bit. And I hope someone more knowledgeable can help us both further our understanding!

 

[Spadez87]

I'm by no means an expert but I'm interested in the topic and think I can contribute some clarity to the discussion. I haven't been tested but I suspect I am an ultrarapid metaboliser due to my atypical experiences with codeine and dextromethorphan.

I can tell you have some understanding of the topic already but I'd first like to clarify some of the terminology.

CYP2D6 is the name of a gene which encodes an enzyme named 'Cytochrome P450 2D6', this is an enzyme which is involved in metabolising a wide range of drugs. Ultrarapid metabolisers have 2 or more copies of the CYP2D6 gene, therefore have higher Cytochrome P450 2D6 (CYP2D6) enzyme activity. Simply, they break down certain drugs faster than average.

From Wikipedia (lazy yeah I know, I used this source because it helped me to understand):



A practical example relevant to us; as you know, codeine is a pro-drug to morphine, amongst others. In order for the body to produce morphine from codeine, it has to be converted by the CYP2D6 enzymes, of which you have many. In ultrarapid metabolisers it is converted more rapidly/effectively, leading to greater effective action by the active metabolite morphine (btw codeine also has other active metabolites such as CG6 which is not metabolised by CYP2D6 enzymes).

A contrasting example; if a poor metaboliser (someone deficient in CYP2D6 activity) uses dextromethorphan (DXM), it will not be converted effectively to dextrorphan (DXO); the main metabolite responsible for its pleasant dissociative effects. DXM itself is active and produces some unpleasant effects. So if you take DXM, you want it to be converted to the more pleasant metabolite DXO, in order to feel it's interesting NMDA antagonist properties. The poor metabolisers simply get the DXM exerting its unpleasant effects, lingering in their system for an extended time because they lack the enzymes to inactivate the DXM and metabolise it to DXO.

I was unable to find out much information about the experiences of ultrarapid metabolisers who've used DXM. But you may be interested to know that I have taken 15mg, which I understand to be a very low dose, and experienced auditory hallucinations. Maybe that has something to do with me possibly being an ultrarapid metaboliser - I would be very interested to hear input from others on this topic.

Hope this helps your understanding a bit. And I hope someone more knowledgeable can help us both further our understanding!

Thanks for the reply man. Yeah I hope someone comes by with some more info also. Fuck I wish I was an extensive metabolizer like 8-10 whites out there.... I got bad knees and a host of mental health problems including bipolar and I can't seem to be medicated. I'm 26 and the last 16 have been a fucking nightmare cuz of Meds

 

[Libertin]

There are alternatives to codeine for those with high CYP2D6 activity.

From CPIC Dosing Guideline for codeine and CYP2D6:

Alternatives that are not affected by this CYP2D6 phenotype include morphine and non-opioid analgesics. Tramadol, and to a lesser extent hydrocodone and oxycodone, are not good alternatives because their metabolism is affected by CYP2D6 activity.

The above link suggests that codeine should be avoided for ultrarapid metabolisers due to potential toxicity issues. However, this depends really on how rapid of a metaboliser you are. 60mg of codeine gets me high and I've been taking it for ~5 years on and off, but mostly ON. I see people talking about 300mg+ recreational doses, and that is incomprehensibly high to me. This is what makes me think I may be an ultrarapid metaboliser and they are merely extensive or intermediate metabolisers.

So maybe if your pain is really impacting your quality of life, and your doctor is understanding to your situation in regards to you being an ultrarapid metaboliser of codeine, then morphine just might be a viable treatment option. Obviously this is something you should discuss with a healthcare professional. Also I feel compelled to say that in practice morphine is often dangerously addictive.

 

[Spadez87]

There are alternatives to codeine for those with high CYP2D6 activity.

From CPIC Dosing Guideline for codeine and CYP2D6:



The above link suggests that codeine should be avoided for ultrarapid metabolisers due to potential toxicity issues. However, this depends really on how rapid of a metaboliser you are. 60mg of codeine gets me high and I've been taking it for ~5 years on and off, but mostly ON. I see people talking about 300mg+ recreational doses, and that is incomprehensibly high to me. This is what makes me think I may be an ultrarapid metaboliser and they are merely extensive or intermediate metabolisers.

So maybe if your pain is really impacting your quality of life, and your doctor is understanding to your situation in regards to you being an ultrarapid metaboliser of codeine, then morphine just might be a viable treatment option. Obviously this is something you should discuss with a healthcare professional. Also I feel compelled to say that in practice morphine is often dangerously addictive.

Yeah 60 mgs codeine gets me high as fuck to.. You could be ultra rapid. Tread carefully man,

Also thanks for the link I'm gonna need new knees at some point and I'm glad there is some pain Meds I can take

 

[Cyn37211]

Hi, I'm new & haven't yet figured out how to get to the profile page, lol! I, too, am an URM. I had a DNA test which showed several gene mutations. My CYP2D6 is duplicated. The way my dr explained this to me is that my body metabolizes opiates too rapidly for me to get the full efficacy of the drug. I have a high tolerance, though I was on the same dosage of MS-Contin for 10 years. My PC recently switched me to Opana, which lasts, on a good day, about 6-8 hours before I start experiencing withdrawal. They also give me morphine IR for breakthrough pain, along with various muscle relaxers (I have Degen. Disk Disease, RA, Osteo-A (why can't I just have one type of arthritis?), Fibro, & migraines. And Diabetes. Also, BiPolar, untreated because I got NMS (Neuroleptic Malignant Syndrome) from Seroquel, which ruined my body. Sorry if this is too long, I tend to be chatty!