Codeine w/ 2D6 & 3A4 inhibited=STRONG → ↑glucuronidation? or more than a pro-drug?!

[killakillakam]

Codeine w/ 2D6 & 3A4 inhibited=STRONG → ↑glucuronidation? or more than a pro-drug?!

Codeine is a pro-drug with active metabolites produced by glucuronidation and morphine via 2D6, and inactive norcodeine via 3A4.

Recently, I consumed ~140mg Codeine but unfortunately, had taken Kava (strong 2D6 and 3A4 inhibitor) and Bupropion (strong 2D6 inhibitor) just before.

Surprisingly, the result was a lengthy, euphoric, stimulating experience comparable to a much stronger opiate.

With a modest understanding of pharmacology, I do not believe that the increased glucuronidation alone could have produced such analgesia. Please correct my ignorance but this experience leads me to believe that perhaps codeine itself may be active in addition its metabolites.

Could someone informed and knowledgeable please comment?

Thank you for your time.

 

[churchpk]

Move to ADD maybe? haha

 

[pasha]

Basic -> Other Drugs

 

[killakillakam]

Guess I'm not going to get any responses.

That's what I get for not posting in 2 years..

 

[RobotRipping]

well that's because morphine isn't the primary drug getting you high! i take cpd 2d6 inhibitors with codeine all the time (well i used to anyway) and enjoyed the buzz so obviously morphine isn't playing a significant role as we had previously thought. Not to mention it also disproves the ceiling theory.

c6g i'm sure you know about but in case you don't go wiki it, that is what is getting you high.

the 3a4 inhibition may have led to a longer duration, not sure about that one though.

 

[killakillakam]

I guess I should have posted in ADD.

Some years ago, there was a trend in research suggesting that codeine itself is active and not just a prodrug for C6G.

I have significant experience with codeine but the experience was comparable to a MUCH stronger opiate (the one I'm thinking of is particularly stimulating and euphoric).

Are there developments in research of the aforementioned theoretical non-prodrug activity of codeine? Or has it been established that codeine has no activity beyond its active metabolites.

 

[sekio]

Codeine itself is weakly active at mu-opioid, less than 1/100 the affinity of morphine. A good portion of its activity probably comes from downstream metabolites. (3- and 6-glucuronide, morphine).
Also of note: codeine and the other opioids are probably also active at e.g. nociceptinR and as histamine releasers, too.

With a modest understanding of pharmacology, I do not believe that the increased glucuronidation alone could have produced such analgesia.

Why do you say that?

It's best to look at the evidence: either there was a drug synergy responsible for making more pleasurable effects (combining codeine and kava would probably do that), or the CYP inhibition just stopped the codeine from being turned to e.g. norcodeine (via 3a4) and more of it turned into the active glucuronides.

Codeine in individuals with low tolerance can be pretty amazingly potent.

 

[killakillakam]

Thank you Sekio.

Why do you say that?

I'm embarrassed to say I can't quite remember/connect the ideas to compose a coherent thesis but... Glucuronidation capacity is comparatively high but I do remember that concurrent morphine glucuronidation inhibits the rate of codeine glucuronidation significantly, so it would seem that codeine glucornidation readily saturates the pathway - which would be rate limiting but not capacity limited.

Anyway, I realize now my post was drivel - your assessment is correct and it may have been just a unique combination of factors.