The CYP2D6 mediated o-demethylation of codeine and the 'ceiling effect'

[MedicinalUser247]

Oxycodone would be the most euphoric in combination. Now I'm done here. Don't ask me how to get higher off opioids.

 

[chippermonk]

Interesting! Any idea how much more would be converted vs the normal conversion amount your body does? I imagine nobody has ever done such studies, and besides, different bodies react different ways
I'm kind of surprised with all the RCs being made in the world that nobody is making glutethimide illegally since it has these sort of effects. Seems like it would be pretty dangerous, of course, and I guess it's still easier for cartels to make fentanyl, so why would they bother?

 

[3DQSAR]

Interesting! Any idea how much more would be converted vs the normal conversion amount your body does? I imagine nobody has ever done such studies, and besides, different bodies react different ways
I'm kind of surprised with all the RCs being made in the world that nobody is making glutethimide illegally since it has these sort of effects. Seems like it would be pretty dangerous, of course, and I guess it's still easier for cartels to make fentanyl, so why would they bother?

That's the problem I found. While there are studies of codeine's increased metabolism in the presence of glutethimide, I was unable to find studies on the other examples mentioned.

But as I've pointed out elsewhere, nobody knows if it's glutethimide itself that is a CYP2D6 inducer (and if so, is one enantiomer responsible)) OR it it one of the metabolites? Because (R) and (S) glutethimide have quite different metabolic fates. It's a more complex puzzle that it first appears to be.

J Med Chem

1975 Jul;18(7):736-41.
doi: 10.1021/jm00241a019.

Synthesis of an active hydroxylated glutethimide metabolite and some related analogs with sedative-hypnotic and anticonvulsant properties​

H Y Aboul-Enein, C W Schauberger, A R Hansen, L J Fischer

PMID: 1151995
DOI: 10.1021/jm00241a019

Above is the paper that studies the QSAR of sedative hypnotic activity BUT of course it doesn't deal with enzyme induction.

 

[chippermonk]

If it's a metabolite, it seems like you might not want to take the glute and codeine simultaneously. Rather, it might be better to take the glute, give it time to metabolize then take the codeine, but before the glute metabolites disappear. I think someone told me that glute is actually a short acting drug, at least as far as primary sedation affects.
But I believe the 4 and dors were taken together (and orally). I don't know know anyone who actually has done them, glute has been off the market for a very long time.
Hard to believe that there are no other substances in existence that do the same thing as glutethimide.

 

[3DQSAR]

If it's a metabolite, it seems like you might not want to take the glute and codeine simultaneously. Rather, it might be better to take the glute, give it time to metabolize then take the codeine, but before the glute metabolites disappear. I think someone told me that glute is actually a short acting drug, at least as far as primary sedation affects.
But I believe the 4 and dors were taken together (and orally). I don't know know anyone who actually has done them, glute has been off the market for a very long time.
Hard to believe that there are no other substances in existence that do the same thing as glutethimide.

That COULD be the case. Ideally one would seek a CYP2D6 inducer that has no other activity. But as far as I know, nobody has studied this aspect.

That the (R) enantiomer of glutethimide is about twice as potent AND faster acting as the (S) enantiomer is interesting. The fact that it's metabolized into 4-hydroxy glutethimide that if even more potent is interesting and those two facts MAY be connected. Or at least I cannot find any paper that kept track of the various actives in the blood.

It's not a medicine that was ever used in the UK. We had our own odd medicines such as clomethizaole and chlormezanone. The latter is still apparently in use in China yet I cannot find a single paper that studies the two enantiomers...

 

[TheJuner]

Oxycodone would be the most euphoric in combination. Now I'm done here. Don't ask me how to get higher off opioids.

Interesting! Any idea how much more would be converted vs the normal conversion amount your body does? I imagine nobody has ever done such studies, and besides, different bodies react different ways
I'm kind of surprised with all the RCs being made in the world that nobody is making glutethimide illegally since it has these sort of effects. Seems like it would be pretty dangerous, of course, and I guess it's still easier for cartels to make fentanyl, so why would they bother?

C

Thread 'Useful papers on the older sedative-hypnotics'

Oct 27, 2020

Wollweber, H. (2000). Hypnotics. Ullmann’s Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a13_533

Hassan Y.Aboul-Enein Analytical Profiles of Drug Substances - Glutethimide Volume 5, 1976, Pages 139-187 https://doi.org/10.1016/S0099-5428(08)60318-4

The determination of (R)- and (S)-glutethimide and the corresponding 4-hydroxyglutethimide metabolises in human serum and urine using a Pirkle-type HPLC chiral stationary phase://doi.org/10.1016/0731-7085(87)80088-2

And an interesting question: https://pubmed.ncbi.nlm.nih.gov/7071114/

I note that...

• clubcard
• Replies: 16
• Forum: Neuroscience and Pharmacology Discussion

• 

This kind of addresses your question.

 

[TheJuner]

That COULD be the case. Ideally one would seek a CYP2D6 inducer that has no other activity. But as far as I know, nobody has studied this aspect.

That the (R) enantiomer of glutethimide is about twice as potent AND faster acting as the (S) enantiomer is interesting. The fact that it's metabolized into 4-hydroxy glutethimide that if even more potent is interesting and those two facts MAY be connected. Or at least I cannot find any paper that kept track of the various actives in the blood.

It's not a medicine that was ever used in the UK. We had our own odd medicines such as clomethizaole and chlormezanone. The latter is still apparently in use in China yet I cannot find a single paper that studies the two enantiomers...

IIrc I'm pretty sure CYP2D6 inducers that aren't CNS depressants do exist but they're incredibly hard to acquire and you wouldn't want to take them. Apparently Haloperidol potentially has some CYP2D6 enzyme inducing effects?

 

[TheJuner]

That's the problem I found. While there are studies of codeine's increased metabolism in the presence of glutethimide, I was unable to find studies on the other examples mentioned.

The absence of other studies isn't of much relevance here. If glutethimide potentiates codeine through acting as a CYP2D6 enzyme inducer which subsequently enables the body to convert a greater portion of the dose of codeine into its active metabolite, morphine, then other opioids which are metabolized by the same enzymatic pathway (that is to say, that are metabolized via CYP2D6 mediated o-demethylation and have their active metabolites yielded through this process) will also be potentiated by glutethimide's CYP2D6 enzyme inducing properties.

 

[TheJuner]

Oxycodone, for example, is metabolized by the CYP2D6 enzyme through o-demethylation which yields oxymorphone, one of oxycodone's main active metabolites which plays a significant role in the analgesic effects of oxycodone. While oxycodone is an active compound on its own, unlike codeine, the importance of the CYP2D6 enzymatic pathway in the metabolism of oxycodone still stands. Another enzyme needs to be mentioned here, though, specifically the CYP3A4/5 enzymatic pathway, which is responsible for converting oxycodone to its less active metabolite noroxycodone. The inhibition of the CYP3A4/5 enzymatic pathway results in a greater analgesic effect of the dose of oxycodone. So I think it is reasonable to assume that the induction of the CYP2D6 enzyme by glutethimide would intensify the analgesic effects of oxycodone through increasing the production of its major active metabolite, oxymorphone. Furthermore, I'd argue that glutethimide would potentiate any opioid in which the activity of the CYP2D6 enzyme is involved in yielding the major active metabolites of the opioid, regardless of whether or not the opioid is inactive on its own (ex. tramadol, codeine) or active on its own (ex. DHC, oxycodone, hydrocodone, etc.)

 

[TheJuner]

Hell, even non-opioid compounds would be potentiated by glutethimide for the reasons listed. DXM is a good example of this (CYP2D6 enzyme mediated o-demethylation is responsible for the formation of DXM's active metabolite, DXO).

 

[Quasimoto]

Hell, even non-opioid compounds would be potentiated by glutethimide for the reasons listed. DXM is a good example of this (CYP2D6 enzyme mediated o-demethylation is responsible for the formation of DXM's active metabolite, DXO).

Yes, I have experienced unpleasant and unwanted potentiation of DXM after a brief regimen of black seed oil, which is also a significant 2d6 inhibitor.

45mg I took for a flu got me high like I had taken 120mg+. I hate DXM, so I wont do that again.

 

[3DQSAR]

I believe the FIRST step would be to discover if it's the (R) or (S) enantiomer (or indeed both) that are CYP2D6 inducers. Then to check to see if it is the drug itself and/or metabolites. The reason I suggest this is because multiple sources note that the (S) enantiomer is around twice as potent (as a sedative) as the (R) enantiomer and is faster acting.

Those last two words MAY be explained by metabolism to the even more active 4-OH glutethimide occur quite quickly which would then make it reasonable to suggest that the metabolite may be the enzyme inducer. Or not. But it seems like a reasonable hypothesis.

While glutethimide is listed in the UNODC, the paper I referenced does conveniently provide a direct (if multi-step) route to 4-OH glutethimide which as far as I can tell, is uncontrolled so could be investigated. The chemistry section does include that worrying phrase 'in good yields' which means one is never quite sure if your yield represents good or bad practical synthesis. Is it supposed to be 60% or 90%? What IS 'a good yield'?

BTW I think it's well worth taking a look at that reference I posted as it's a useful index paper i.e. it references virtually every other paper useful in the study of glutethimide. It's also worth noting that all 4 isomers of 2-ethyl-4-hydroxy-2-phenylpentanedinitrile appear to be commercially available so one could in theory even test if the 4-OH remains chiral in vitro.