Sooo, oxycodone taken orally is metabolized by CYP4502D6 into oxymorphone, and then metabolized by CYP4503A5 into noroxycodone.

Now here's where I need a little help. I think it goes,

Oxymorphone > Oxycodone > Noroxycodone.

Does that seem right? I'm not 100% sure where the noroxycodone fits in there.

So, if I'm taking a cytochrome inhibitor (budeprion, cimetidine, etc) to potentiate opiates as I have for many years, this is preventing my body from creating the oxymorphone? Isn't that bad?

Should maybe my goal be to cease inhibition of 2D6 to allow the oxycodone to be metabolized into oxymorphone, and then maybe try to inhibit 3A5 too keep the oxymorphone around?

Mods can move this if they believe I'd receive better responses in lab tips.

Thanks,
mike

Ok, you're almost correct. Except it's more like this:

Oxycodone
/ 2D6/ \3A4|5\
Oxymorphone Noroxycodone

As far as I know, oxymorphone is not metabolized into oxycodone at any point, but the OPPOSITE is true. (Oxycodone >> Oxymorphone)

However, it's worth noting that only a VERY small portion of your oxycodone dose (like 2%) makes the transition into oxymorphone.

However, this is when noone is fucking around.

If you're taking a broad P450 inhibitor, then you're going to have roughly the same ratio of conversion to oxymorphone and noroxycodone as you would with out it, but the oxycodone will take significantly longer to be converted. (Good thing, as MOST of it turns into worthless noroxycodone).

However, if you combine a broad spectrum inhibitor with a 3A* selective inhibitor, you get oxycodone that lasts longer AND which has a higher rate of conversion to oxymorphone because the preferred 3A5 pathway is clogged.

What is a (relatively) selective 3A* inhibitor?

White grapefruit juice! (preferably from concentrate)

Pop 800mgs of cimetidine, and chug a few glasses of white grapefruit juice about 45 minutes before dosing.

Also, apparently any kind if pH differences can effect cimetidine's absorption, and grapefruit juice is apparently very alkaline once in your stomach, so you might wanna space the two out. (Tagamet first)

My little description was using greater than / less than signs (ie. oxymorphone is best, oxycodone is 2nd, and noroxycodone sucks balls). I was already aware of how it's metabolized, except that I thought it was only one 3A* enzyme involved.

Now, cimetidine is my normal inhibitor, but lately I've been using my wellbutrin when I take oxys or adderall. I believe budeprion is only a 2D6 inhibitor, albeit a potent one. So, my real question was, is this stopping me from metabolizing the oxycodone into oxymorphone?

Now, grapefruit juice, I thought that was one of the most broad inhibitors. Assuming that you're correct (I'll verify after I finish this), that would just prevent the oxymorphone from being metabolized into noroxycodone, correct?

So, lots of grapefruit juice for that. But how do I increase the amount of oxycodone that is converted to oxymorphone? Do we have something the opposite of a 2D6 inhibitor?

Lastly, if only 2% is indeed metabolized into oxymorphone, how is the rest of the oxycodone removed from the body? Just excreted, rather than metabolized?

If you have links, throw them at me. Most of what I'm finding is abstracts for scientific articles I'd have to pay for.

mike

Edit: White grapefruit juice is indeed a reasonably selective inhibitor of 3A* enzymes. Now I guess I just need to know how to best fuck with 2D6, and maybe some links to read.

My little description was using greater than / less than signs (ie. oxymorphone is best, oxycodone is 2nd, and noroxycodone sucks balls). I was already aware of how it's metabolized, except that I thought it was only one 3A* enzyme involved.

Now, cimetidine is my normal inhibitor, but lately I've been using my wellbutrin when I take oxys or adderall. I believe budeprion is only a 2D6 inhibitor, albeit a potent one. So, my real question was, is this stopping me from metabolizing the oxycodone into oxymorphone?

Now, grapefruit juice, I thought that was one of the most broad inhibitors. Assuming that you're correct (I'll verify after I finish this), that would just prevent the oxymorphone from being metabolized into noroxycodone, correct?

So, lots of grapefruit juice for that. But how do I increase the amount of oxycodone that is converted to oxymorphone? Do we have something the opposite of a 2D6 inhibitor?

Lastly, if only 2% is indeed metabolized into oxymorphone, how is the rest of the oxycodone removed from the body? Just excreted, rather than metabolized?

If you have links, throw them at me. Most of what I'm finding is abstracts for scientific articles I'd have to pay for.

mike

Hmm. Wellbutrin only works as an inhibitor when you have 3A4 LOCKED THE FUCK DOWN. Because Wellbutrin is SUCH a good 2D6 inhibitor, if you don't have 3A4 fucking stuffed, you're going to get a lot more noroxy then you want.

And Grapefruit juice would(and DOES!!!) prevent oxyCODONE, not oxyMORPHONE from turning into noroxycodone, yes.

Oxymorphone does not metabolize into oxycodone or noroxycodone.

Moving on, THIS (http://opioids.com/oxycodone/metabolites.html) piece states that the ONLY oxycodone metabolites in humans are noroxycodone and oxymorphone.

Since Oxymorphone is such a small metabolite, it's only logical to assume that noroxycodone must be a HUGE metabolite. A small amount of the oxy is probably excreted untouched, as well.

However, THIS (http://www.jenniferschneider.com/articles/Conv_of_Oxycodone_7_20_7.html) article seems to imply that the ratio of conversion from oxycodone to oxymorphone can vary SIGNIFICANTLY, and that the average in humans may be around 15%.

Hmm. Wellbutrin only works as an inhibitor when you have 3A4 LOCKED THE FUCK DOWN. Because Wellbutrin is SUCH a good 2D6 inhibitor, if you don't have 3A4 fucking stuffed, you're going to get a lot more noroxy then you want.

And Grapefruit juice would(and DOES!!!) prevent oxyCODONE, not oxyMORPHONE from turning into noroxycodone, yes.

Oxymorphone does not metabolize into oxycodone or noroxycodone.

Moving on, THIS (http://opioids.com/oxycodone/metabolites.html) piece states that the ONLY oxycodone metabolites in humans are noroxycodone and oxymorphone.

Since Oxymorphone is such a small metabolite, it's only logical to assume that noroxycodone must be a HUGE metabolite. A small amount of the oxy is probably excreted untouched, as well.

However, THIS (http://www.jenniferschneider.com/articles/Conv_of_Oxycodone_7_20_7.html) article seems to imply that the ratio of conversion from oxycodone to oxymorphone can vary SIGNIFICANTLY, and that the average in humans may be around 15%.

Whoops, I had a misunderstanding. I thought it was a linear progression from oxycodone to oxymorphone to noroxycodone. I now see that oxycodone metabolizes into both oxymorphone and noroxycodone.

Translating this to practical use, it remains the same. I still want to be inhibiting 3A4|5 to prevent noroxycodone from taking over, but I want some way to enhance 2D6 to increase production of oxymorphone. Can you offer any advice in regards to that?

Now, you say that for me to take my oxys with my wellbutrin, I'm going to want to make sure I have the 3A* enzymes inhibited as much as possible. Is this because if I were to only inhibit 2D6, all of the oxycodone would be metabolized into noroxycodone, and almost none would become oxymorphone, and that this wouldnt even really increase the duration of oxycodone?

That would explain why my oxys didnt feel all that great last night. It was my first time using wellbutrin with a narcotic painkiller, and I didn't get around to this research until today.

But yeah, I have a much better understanding of this shit overall, but I just need to know a way to alter the action of 2D6 to increase production of oxymorphone. Now, if I concluded correctly two paragraphs back that inhibiting only 2D6 would force all oxycodone to be metabolized by 3A* into noroxycodone, would the same be true if switched around? If I completely block 3A4|5, will a larger percentage be metabolized into oxymorphone?

mike

Whoops, I had a misunderstanding. I thought it was a linear progression from oxycodone to oxymorphone to noroxycodone. I now see that oxycodone metabolizes into both oxymorphone and noroxycodone.

Translating this to practical use, it remains the same. I still want to be inhibiting 3A4|5 to prevent noroxycodone from taking over, but I want some way to enhance 2D6 to increase production of oxymorphone. Can you offer any advice in regards to that?

Now, you say that for me to take my oxys with my wellbutrin, I'm going to want to make sure I have the 3A* enzymes inhibited as much as possible. Is this because if I were to only inhibit 2D6, all of the oxycodone would be metabolized into noroxycodone, and almost none would become oxymorphone, and that this wouldnt even really increase the duration of oxycodone?

That would explain why my oxys didnt feel all that great last night. It was my first time using wellbutrin with a narcotic painkiller, and I didn't get around to this research until today.

But yeah, I have a much better understanding of this shit overall, but I just need to know a way to alter the action of 2D6 to increase production of oxymorphone. Now, if I concluded correctly two paragraphs back that inhibiting only 2D6 would force all oxycodone to be metabolized by 3A* into noroxycodone, would the same be true if switched around? If I completely block 3A4|5, will a larger percentage be metabolized into oxymorphone?

mike


EXACTLY! :D

Yep, spot on. In theory, if you were to completely shit on 3A4, 2D6 would be the ONLY possible metabolic pathway. This means that you would have significantly higher oxymorphone levels, and also your oxy would last ALOT longer.

As far as your wellbutrin situation: Yeah, you're going to get alot more useless noroxycodone, but the oxycodone will last longer because the amount that would have been taken care of by 2D6 now has to 'wait in line' for 3A4.

So, it works, but there are much better ways of going about it.

Now, you talk of the opposite of a 2D6 inhibitor. These are called inducers. In theory, and inducer would be GREAT, right?

Strongly inhibit 3A4, then induce 2D6 so that you have no noroxycodone and ALOT of oxymorphone!

Only problem is, 2D6 happens to be one of the two enzymes that metabolizes oxymorphone into an inactive metabolite.

So as soon as you get all this awesome oxymorphone, your revved up 2D6 will fuck it up.

If you want to try it out anyway, dexamethasone (http://en.wikipedia.org/wiki/Dexamethasone), carbamazepine (http://en.wikipedia.org/wiki/Carbamazepine), phenobarbital (http://en.wikipedia.org/wiki/Phenobarbital), phenytoin (http://en.wikipedia.org/wiki/Phenytoin), ritonavir (http://en.wikipedia.org/wiki/Ritonavir), and rifampin (http://en.wikipedia.org/wiki/Rifampin) are 2D6 inducers.

Okay, so from what I got out of this, I have two choices:

1. Inhibit 2D6 and 3A4|5. This would increase the length of time that the oxycodone is present in my system, but wouldn't give me the oxymorphone I so desire.

2. Inhibit only the 3A* enzymes. This would increase both the duration of oxycodone and the amount converted into oxymorphone.

Are my conclusions correct here?

Sounds like I'd be better off skipping the cimetidine, and just going with some grapefruit juice, but I could be wrong?

Your final thoughts?

mike

Edit: Wait, why from concentrate? I thought that the enzyme inhibitors were much much much more present in non-concentrate, or best, freshly made juice.

All your thoughts there are correct. I personally dose with cimetidine AND white grapefruit juice, but if you want more oxymorph you could nix the tagamet.

I have no idea why, but I CLEARLY remember reading that naringin, bergamottin, and dihydroxybergamottin(the 3A4 inhibitors) are present in higher concentrations in juices reconstituted than they are in fresh squeezed juices.

All your thoughts there are correct. I personally dose with cimetidine AND white grapefruit juice, but if you want more oxymorph you could nix the tagamet.

I have no idea why, but I CLEARLY remember reading that naringin, bergamottin, and dihydroxybergamottin(the 3A4 inhibitors) are present in higher concentrations in juices reconstituted than they are in fresh squeezed juices.

if everything goes perfectly you do realize you'll be metabolizing roughly 7-50X( given the variance of metabolism levels varying between 2-15%) the amount of oxymorphone in both exposure and duration, but without the inducers the high would be the same strength merely MUCH longer. With the inducers would the duration of the effects be the same length and just MUCH stronger or still more drawn out than normal.


I guess my question is how drastically does the inducer raise the metabolism rate of oxymorphone? 2X as fast? 130% as fast? 10X as fast?

All your thoughts there are correct. I personally dose with cimetidine AND white grapefruit juice, but if you want more oxymorph you could nix the tagamet.

I have no idea why, but I CLEARLY remember reading that naringin, bergamottin, and dihydroxybergamottin(the 3A4 inhibitors) are present in higher concentrations in juices reconstituted than they are in fresh squeezed juices.

Well, a quick googling shows various other forums discussing this, and everyone seems to say that fresh beats concentrate (several times the strength). I didn't see any scholarly articles offhand (though, like I said, it was just a quick look), so I'm not gonna post any links.

This one, I'm pretty sure I'm right about, though if you find a reference contradicting me, please post it.

I'll do some fucking around with inducers when I have more OC to spare, maybe post some results.

Personally, I think this thread should be archived, or the information posted somewhere by someone with enough time and motivation to do so. Maybe a bit more discussion will come about regarding inducers, first, though.

mike

if everything goes perfectly you do realize you'll be metabolizing roughly 7-50X( given the variance of metabolism levels varying between 2-15%) the amount of oxymorphone in both exposure and duration, but without the inducers the high would be the same strength merely MUCH longer. With the inducers would the duration of the effects be the same length and just MUCH stronger or still more drawn out than normal.


I guess my question is how drastically does the inducer raise the metabolism rate of oxymorphone? 2X as fast? 130% as fast? 10X as fast?

I'm sorry, I don't understand you first question.

I understand your last question, but I haven't got a clue as to the answer, and can't seem to find any literature on those details...sorry. :p


Mksnowboarder:

http://dmd.aspetjournals.org/cgi/reprint/25/11/1228.pdf

This study clearly shows that white grapefruit juice from concentrate contains more than DOUBLE the amount of 6,7 dihydroxybergamottin, the main inhibitor, as fresh squeezed white grapefruit juice.

I'm sorry, I don't understand you first question.

I understand your last question, but I haven't got a clue as to the answer, and can't seem to find any literature on those details...sorry. :p


Mksnowboarder:

http://dmd.aspetjournals.org/cgi/reprint/25/11/1228.pdf

This study clearly shows that white grapefruit juice from concentrate contains more than DOUBLE the amount of 6,7 dihydroxybergamottin, the main inhibitor, as fresh squeezed white grapefruit juice.


my first question was that if only 2% of what you quickly take away from an oxy is the "good stuff" Than wouldnt metabolizing everything into oxymorphone lead to the pill being 50X as strong? Not only that but the inducer would make the pill be metabolized faster... Isn't there a danger there?

my first question was that if only 2% of what you quickly take away from an oxy is the "good stuff" Than wouldnt metabolizing everything into oxymorphone lead to the pill being 50X as strong? Not only that but the inducer would make the pill be metabolized faster... Isn't there a danger there?

Uhhh, you's really gots to works on how you's phrases this stuff, G. Let me take a crack at this.

Well, N0 WARNING cited two sources, one claiming 2% of the oxycodone ingested was metabolized into oxymorphone, and the other claiming that up to 15% may be so metabolized. Thats where your first idea originated, I'm assuming, but after that it gets a little fishy.

First of all, it would probably be impossible to metabolize "everything" into oxymorphone, no matter what you did with your liver enzymes. And 50x as strong? I don't know where you got that number, but I doubt it's even close to accurate.

But yeah, there's a danger involved in potentiation. There always is. So make sure you know what you're doing, and don't bother fucking around with it if you still get high off a 5mg vicodin. And yeah, using an inducer combined with an inhibitor is probably more dangerous than an inhibitor alone.

mike

Isnt noroxy inactive>?

my first question was that if only 2% of what you quickly take away from an oxy is the "good stuff" Than wouldnt metabolizing everything into oxymorphone lead to the pill being 50X as strong?

Because oxycodone is itself an active opioid, the answer is no. Doing some quick rounding (98% -> 100%), if oxymorphone has 5 times the potency of ingestion of oxycodone, the pill could AT MOST be 5x stronger. Correcting for the rounding error means it will be closer to 4.99x stronger, and correcting for... other effects... means that you could inactivate it completely, with enough work.

On to the next question...

I guess my question is how drastically does the inducer raise the metabolism rate of oxymorphone? 2X as fast? 130% as fast? 10X as fast?

Well, that's... very complex. NoWarning cleared up most of the stuff in this thread (such as the nonrealkylation of desmethylcodine derivatives).... but there's one other factor...

In non-codiene-derived opioids, the only effect of 2D6 is the effect concurrently provided by 3A5 - n-demethylation from the tertiary to the secondary amine, which inactivates it. That's the only reason, in fact, that anyone gives a fuck about 2D6 - it's the main deactivator of things like morphine and heroin through this mechanism, and hence why people put so much work into inhibiting it.

No one wants to keep their codeine from being active.

Unfortunately, since it's the same enzyme, there will be a 1:1 ratio between the change in rate at which CYP2D6 converts codeine/oxycodone into morphine/oxymorphone, and the rate at which CYP2D6 converts codiene/oxycodone/morphine/oxymorphone into the inactive norcodiene/noroxycodone/normorphine/noroxymorphone. Change one, you change the other... though blocking 3A5 may be helpful.

If you'd like to commit suicide and donate your organs to Joe the Pedo, I'll happily soak slices of the-liver-formerly-known-as-yours in various solutions to see if physiologic changes - pH, oxygen saturation, whatever - can affect CYP2D6 in ways which skew the ratios of its byproducts - here, oxymorphone versus noroxycodone.

Until this happens, however, or until murder is legalized and I just begin a process of live organ harvesting in the name of science, the 2D6 will do what it does - everything it does - equally.

This means that if you want to potentiate oxycodone, you block them both. If you want to maximize oxycodone conversion OR potentiate codeine, you only block 3A5 and any other pertinent p450 subtypes, but NOT 2D6.

If you want your oxymorphone high from oxycodone to be more-predominant, but much less potent and much shorter, you would block 3A5 and induce 2D6. I'd imagine this is where overdoses would be more likely to occur, as people try to compensate for their pills being 1/10th* as potent before finding out that their calculations on the rate of induction were slightly off. That's a danger...

* completely arbitrary random number, btw.

If you'd like to commit suicide and donate your organs to Joe the Pedo, I'll happily soak slices of the-liver-formerly-known-as-yours in various solutions to see if physiologic changes - pH, oxygen saturation, whatever - can affect CYP2D6 in ways which skew the ratios of its byproducts - here, oxymorphone versus noroxycodone.

.
i loled! I love it joe pedo can always make this somewhat dry scientific stuff enjoyable, funny, and interesting at the same time

Hey, JoePedo, maybe you can give me a hand here. I'm looking to read up more and enhance my understanding of this subject. Can you provide me with any pertinent links?

This might be too much to ask of this forum, but you seem to know what you're talking about. I have an idea that I'd like your thoughts on.

Okay, so, how about we start by inhibiting the crap out of 3A* to prevent any noroxycodone production with massive amounts of grapefruit juice.

Then, we take a 2D6 inducer to allow creation of mass oxymorphone.

Now here's where I need a hand. After allowing the 2D6 inducer to metabolize a sufficient amount of oxycodone into oxymorphone, we take a shitload of cimetidine (more than used for normal 2D6 inhibition) to shut off 2D6 after it's done what we needed it to do. This would prevent 2D6, at least, from destroying our precious oxymorphone (I'll look around, but if someone gets to this first, what's the other enzyme responsible for metabolizing oxymorphone, and how can we inhibit it?).

The real remaining question is, how long should we let 2D6 run rampant before shutting it off? It'd take some practice with timing, and you'd have to know how long it would take your body to put the tagamet to use so that you could shut off 2D6 at just the right time to allow for maximum oxymorphone production while still shutting it off in time to prevent the same oxymorphone from being removed from your system?

I dunno, I was brainstorming this as I lay in the homeless shelter last night. N0 WARNING and JoePedo seem to have a great deal of knowledge on this subject, and if they have an answer to help me with this final problem, hell, we have just maximized the value of oxycodone. I'd be willing to compile all this information into a website, but perhaps the mods would like to archive this? You don't often have discussion this valuable on this forum anymore...

mike

Mike, that is a phenomenal idea, in theory at least. I had a very similar idea to that a few years back: Induce CYP2D6, eat a bunch of codeine, and then inhibit the hell out of 2D6. Theoretically, this would massively increase the ratio of codeine -> morphine, and maybe even raise the 'ceiling effect' on codeine so people like me could get high off it again. ;)

However, I could NEVER get it right/ >_<

I tried several times, and wasted alot of cash on overpriced T3s. I always got a sub-par buzz.

My method was to take 2 pills of my aunt's rifampicin(don't remember the mg), an hour later eat 210mg codeine, 30 minutes later insufflate 90mg bupropion. (half an XL)

It never worked like I thought it would; so even though it SOUNDS great, it would probably be VERY difficult to pull off with oxycodone as well. Especially since everybody will have a different amount of time to process all the codeine\oxy.

It could be that I just didn't give the codeine enough time.

And before anyone gives me shit for taking my aunt's meds, I was like fucking 16 at the time. We all do stupid shit at some point.

Thanks for the props, man; great minds think alike, eh?

I do understand how difficult this would be. Even after you determine your body's rate of absorption and metabolism for each substance involved and figure out general timing stuff, you have to take into account that all these things will be fluctuating to some extent.

Hell, I'm gonna be playing with potentiators like I have for the past two years, regardless. So why not use my increasing knowledge of biochemistry to at least search for the perfect combination?

Maybe someone with the resources to actually measure blood levels of the chemicals involved will take an interest in this case and point me in the right direction (glances around for JoePedo).

But if anyone else is interested in fucking with this shit, do let me know, and we can compare notes.

I'm gonna write up something and throw it on geocities so I can link people interested in potentiation to it in the future.

mike

So what im getting from this discussion is that i should inhibit both CYP4503A4(+5) and CYP4502D6. But i should focus on inhibiting 3A4|5 as much as possible and inhibiting 2D6 as well but not so thoroughly.

This will save as much oxycodone as possible from being metabolized into noroxycodone. It will also slow 2D6 so as to keep the oxy from being metabolized quickly, and when it is metabolized it will be turned into oxymorphone. So long as it is still inhibited, then the metabolism of oxymorphone will also be slower than normal.

The trick seems to be inhibiting 3A4|5 so completely that although 2D6 is also inhibited, it will still be more available than 3A4|5. Can someone reccomend dosage per units of body mass to acheive this balance? Also, what are the other enzymes that metabolize oxymorphone, and what can one injest to inhibit them without negatively affecting the other metabolic processes discussed.

bump for good thread & to get my question answered.

Well you've got the concept spot-fucking-on. I really couldn't have said it better myself.

As for your second question however, I'm as clueless as you.

For dosage, I find that 800mg TagametHB and 2 12oz bottles of tropicana 100% white grapefruit from concentrate noticeably extend and better the high when both are taken around an hour prior to dosing.

No enzymes other than 3A4 and 2D6 act on oxycodone in the CYP450 set, and that is where my enzyme expertise ends. If there are more enzymes (and there may well be) I have no knowledge of them.