Codeine metabolism

[ampakine]

Here is a chart of the enzymes responsible for metabolising codeine and its metabolites:

so as you can see, on top of codeine being metabolised into morphine by CYP2D6 and CYP2D7, its also converted into norcodeine (an opioid with little or no potency) by the CYP3A4 enzyme. The obvious route to potentiating codeine would be inhibiting CYP3A4 and increasing activation of CYP2D6 and 7. Firstly inhibition of CYP3A4. Heres a list of known substrates, inhibitors and inducers of the enzyme:
http://en.wikipedia.org/wiki/CYP3A4#CYP3A4_substrates
For anyone that doesn't know the substrates are the compounds that the enzyme metabolises, inhibitors are compounds that prevent the enzyme from doing its job and inducers are compounds that make the enzyme work even better. Thus to potentiate codeine you want to take inhibitors and avoid taking any of the inducers. Also be careful if you are on any of the substrates other than codeine because inhibitors will potentiate them too.

Alright so heres info on CYP2D6:
http://en.wikipedia.org/wiki/CYP2D6#CYP2D6_ligands
glutethimide is a well known codeine potentiator
http://en.wikipedia.org/wiki/Glutethimide#Recreational_use
that supposedly increases the potency of codeine by 300%. I hear this combo has some extremely harmful side effects and is easy to overdose on but I don't know the pharmacology behind that I'll have to do some research on this. If those claims are true though this combo should be avoided.

Anyhow I'm interested in testing out new codeine + inhibitor/inducer. Grape fruit juice is a well known inhibitor of CYP3A4. I haven't checked the reference but according to this:
http://www.medscape.com/viewarticle/429776_7
ecinachea extract has been shown to inhibit the enzyme in vitro. Heres a different study
http://www.hindawi.com/journals/ecam/2011/213021/
in which they conclude:

We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

what does that mean "CYP3A4 transcriptional levels"?

I also heard that St Johns Wort is a CYP3A4 inhibitor but according to this:
http://dmd.aspetjournals.org/content/32/5/512.full
it does the opposite, it increases the activity of 3A4. Heres a quote from the end of the discussion:

Our studies clearly document the potential for the St. John's wort constituent hyperforin to induce CYP3A4 and CYP2C9 upon chronic exposure. Combined, both enzymes are responsible for the metabolism of a wide variety of commonly prescribed medications worldwide. Decreased blood plasma concentrations of drugs that may result from induction of these enzymes has the potential to seriously alter desired drug therapy outcomes in patients concurrently taking St. John's wort. Although we have shown that hyperforin has the potential to inhibit CYP3A4, particularly after single exposure at high concentrations, the inductive effect predominates with chronic exposure. Furthermore, our studies have demonstrated the utility of human hepatocyte cultures in clarifying induction/inhibition discrepancies that are related to how a compound affects a drug-metabolizing enzyme(s).

so it doesn't look good for St Johns Worts codeine potentiating ability.

Anyhow there are plenty of known CYP3A4 inhibitors on that list that haven't been tested as codeine poteniators. Plenty of them are antibiotics which would wipe out your intestinal bacterial fauna and pretty much all symbiotic bacteria in your body so they're probably not the best option. I don't know anything about protease inhibitors but something tells me its best to stay the hell away from them. Antifungals on the other hand might be worth trying. As far as I know humans don't have any symbiotic fungal cells living in them. Can anyone here get their hands on one of those azole antifungals?

As for inducers, the same hazards associated with glutethimide may apply to inducers in general so I'm gonna research this more before playing around with CYP2D6 inducers.

 

[titstypedthis]

alcolol is apparently a CYP2D6 inducer, i'm unsure of whether its the direct action of alcohol or part of its metabolism though.

so perhaps on your next painful hangover give that CWE a go, for science!

 

[grrr8Dane]

^^^ "give that CWE a go, for science!" HAHAHAHA!

titstypedthis is right, Ethanol is a CYP2D6 inducer. Also, St. John's Wort is a CYP2D6 inducer and while it is a CYP3A4 inducer as well, it (possibly) does have the ability to potentiate Codeine. Somebody please correct me if I am wrong, but inhibiting production of CYP3A4 in efforts to prevent Codeine from metabolizing into Norcodeine will not cause more Codeine to be metabolized into Morphine, rather, more Codeine will be excreted unchanged.

I've used CYP2D6 inducers (Ethanol) and other substances (Carisoprodol in particular) to potentiate Codeine and I can say for certain that for me, they worked.



edit: this study suggests that St. John's Wort may have no effect on CYP2D6 whatsoever, however, I have CYP450 table (updated in 2003) that indicates St. John's Wort has demonstrated clinically significant ability to induce CYP2D6 - I can upload it if it is of interest to someone.

 

[adder]

CYP3A4 would have another "positive" impact on codeine metabolism or rather further metabolism of its metabolites. CYP3A4 is also responsible for N-demethylation of morphine (normorphine has like 10% potency of morphine). Would that make more morphine to be metabolized to M6G or not, it would boost and prolong effects. Also, if CYP3A4 inhibition means "pushing" the drug to conjugation with glucuronic acid, then maybe more C6G is produced which adds to codeine analgesia (cf. articles with conclusions that people lacking CYP2D6, can still feel analgesia after ingestion of codeine).

Generally speaking one would want to "push" through 2D6 as much codeine as possible and the rest of codeine to be "pushed" through UGT2B7 so as much unmetabolized codeine as possible is metabolized to C6G and not norcodeine.

I can't virtually see such a perfect manipulation happening but it's always nice to theorize.

 

[fluffyrude]

MORPNINE PATCHES AND CONDINE PHOSPHATE
is it dengrous to take a 350mg dose while on time release morphine patchs(35ug/h) espically as the codine turns to morphine in the liver

 

[Alcyone]

MORPNINE PATCHES AND CONDINE PHOSPHATE
is it dengrous to take a 350mg dose while on time release morphine patchs(35ug/h) espically as the codine turns to morphine in the liver

Not really sure what you mean, but I'm guessing you're talking about taking 350 mg codeine phosphate while you're on transdermal patches of some sort?

Those "morphine patches 35 ug/h" sound to me like buprenorphine patches, or perhaps fentanyl. There's no such thing as morphine 35 µg/h patches. If they're buprenorphine, taking codeine would be a complete waste. If they're fentanyl, be careful so you don't OD on us. 350 mg codeine is a fairly high dose.

 

[nj754]

what does that mean "CYP3A4 transcriptional levels"?

It means the amount of CYP3A4 that gets transcribed from DNA. In other words, the amount of CYP3A4 that gets made.

Anyhow there are plenty of known CYP3A4 inhibitors on that list that haven't been tested as codeine poteniators. Plenty of them are antibiotics which would wipe out your intestinal bacterial fauna and pretty much all symbiotic bacteria in your body so they're probably not the best option. I don't know anything about protease inhibitors but something tells me its best to stay the hell away from them. Antifungals on the other hand might be worth trying. As far as I know humans don't have any symbiotic fungal cells living in them. Can anyone here get their hands on one of those azole antifungals?

You can buy ketoconazole and itraconazole easily without a prescription in Mexico. I have in fact done this in furtherance of my own pharmacology research. They upset your stomach a little bit, but otherwise they are pretty safe and free of side effects.

As for inducers, the same hazards associated with glutethimide may apply to inducers in general so I'm gonna research this more before playing around with CYP2D6 inducers.

I think trying to potentiate codeine by messing with cytochrome P450 enzymes is a dead end. 80% of it already gets conjugated into codeine-6-glucuronide, which is active. Blocking CYP3A4 is only going to cause a little bit more to be conjugated, and wouldn't change the situation with the morphine, which is made in amounts too small to be felt. There are no other potent CYP2D6 inducers like glutethimide was said to be. Carbamazepine can induce 2D6 a bit, but it has some annoying and potentially-dangerous side effects, and the effect on 2D6 is likely not that big.