My theory as to why grapefruit drug indirectly leads to potentiation of codeine.

[sarbanes]

My theory is that this works because of some sort of rebound, enhanced metabolism potential (takes time for homeostasis after the drug grapefruit treatment). So the grapefruit's drug effect directly inhibits enzyme necessary for conversion to morphine. After this wears off (~5 hours), there is a surge of enzyme, and it comes back with a vengeance (since synthesis itself was never inhibited). It then takes some time for the body to get back to normal, and this is what you are taking advantage of 5 hours later. Just a theory, but the only one which makes sense. Very simple, actually. Same would probably be true of tramadol?

[Ethyl]

not true. grapefruit juice effect on enzymes can last up to weeks .

[sarbanes]

please delete me (and the one above me as well!)

[sarbanes]

Originally Posted by Ethyl

not true. grapefruit juice effect on enzymes can last up to weeks .

No, you are dead wrong, and here is why. The acute effects (>90%) occur within our ~5-28 hour time frame, and the remaining 10%, take "up to weeks" (your own words) to baseline. This is the same reason traces of drugs can be detected in urine/blood for "up to weeks". Not that they exist in any pharmacologically significant amounts. Just because some drugs can be seen for many days via GC/MS doesn't mean you are high for a month, lol.


Oh, and the other smart thing you said was "up to". Lets say (for sake of your assertion), that the above (my assertion) is not true at all. Let's say (for your benefit), that the effects of the grapefruit are all on or off, be it 5 hours, or two weeks. Even though this is an unlikely scenario (as this is not how the human body works), you said "up to", which means one hour, 5 hours, or "up to" two weeks. So your own language doesn't negate my hypothesis (above). I just pointed this out to show your poor choice in words regarding how I think you intended to convey some information (from your brain, onto this forum). You said it takes "up to" two weeks, which means it could be much shorter (like 5 hours), or much longer (like "up to" weeks). Not that this matters at all, as I have already pointed out that acute effects generally ramp down exponentially (hence a drug’s "half life"), and a plateau remainder of otherwise pharmacologically insignificant amounts of actives which slowly leaves (this is why drug tests detect miniscule amounts of drugs days or weeks later, even though the drugs being detected have LONG lost their effect). If what I think you MEANT to say (not what you did say) was true, then logic would follow that because THC can be detected for "up to" weeks in your pee, you must be high for weeks at a time.
I'll post references later. Just love your post, BTW =) Great work!

[Paracelsus]

In your meticulous research you are so passionately defending, you missed several crucial points. Your theory is far from current knowledge (and certainly not "the only one which makes sense"). This thread contributes to the already pronounced confusion about this topic (in the online drugs community), and should be deleted.

So the grapefruit's drug effect directly inhibits enzyme necessary for conversion to morphine.

The theory fails from the start: grapefruit juice does not inhibit CYP2D6 (which is the enzyme that catalyzes O-demethylation of codeine into morphine). It inhibits CYP3A and CYP1A2, the former explaining its potentiating effect on codeine (CYP3A is the major metabolic pathway which N-demethylates codeine into the inactive norcodeine). Use the search engine, I wrote a thread about this in the Pharmacology forum.

After this wears off (~5 hours), there is a surge of enzyme, and it comes back with a vengeance (since synthesis itself was never inhibited).

This claim is useless without references for the following: a) enzyme inhibition lasts for 5 hours, and b) enzyme is induced by inhibitors after inhibition wears off. I won't waste too much time on this as your theory is flawed to begin with. But grapefruit juice was shown to inhibit enzyme activity for several days (still being significant after three days, if I recall correctly - check my aforementioned thread for the data), although it was CYP3A and not CYP2D6. Also, CYP2D6 is generally regarded as non-inducible (CYP2D6 activity was never induced in vivo) so the rebound is unrealistic.

Reputation Comments on this post:

Good Job

[sarbanes]

Well, SAW, I'm not the grapefruit expert here - just hypothesizing. If you really want to delete it, why don't you go ahead...u r a moderator, you know

Reputation Comments on this post:

if you're not an expert don't purport to be one

[Tortoise]

Sarbanes, your theory is the Adam & Eve to Paracelsus' Darwinism.

[sarbanes]

Originally Posted by Tortoise

Sarbanes, your theory is the Adam & Eve to Paracelsus' Darwinism.

That is SO CLEVER, I mean, I'M JUST FLOORED!

Reputation Comments on this post:

Yoou seem to have some good things to offer, but your attitude seriously lets you down. Think before you post & don...

[sarbanes]

If you go into google scholar, and search "grapefruit +codeine", the result 5th one down "Codeine intoxication associated with Ultrarapid CYP2D6 Metabolism" is really an awesome reading. Grapefruit juice and alcohol were prohibited 3 days prior in the study patients, for obvious reasons. Genetics seems to play a role here. Perhaps its a combination of some genetics and environmental factors (grapefruit).

Wait, I hope I'm not sounding too biblical and(or) Adam & Eve'ey. Seriously, does anyone really think I sound of that?!?! I find that very off and obscure.

[Mint boi]

Ok... you know he wasn't saying you sound biblical right?

I think its pretty well accepted that grape fruit juice potentiates codeine by inhibiting CYP3A. Paracelsus has said it all pretty well above.

[Paracelsus]

I've read that report - it's also in our file archive. I also found it interesting, but it is a case report, no actual study/trial. Grapefruit isn't mentioned in the document (only in a citation at the end). In that patient, many factors caused his overdose. He had ultrarapid CYP2D6 (more morphine), inhibited CYP3A from a drug I can't remember right now (CYP3A inhibition potentiates morphine), and kidney failure (no elimination of morphine). The perfect combo for an overdose.

I don't think you sounded biblical at all (the comment in post #7 is indeed pointless). Otherwise you would've defended your theory with stuff like "grapefruit juice works in mysterious ways" and that the researchers that came up with facts refuting your theory were posessed by the Devil

[sarbanes]

Thank you, Paracelsus. I do believe in god, but that has nothing to do with my belief in evolution. I suspect on a higher (godly) level, evolution/creationism need not necessarily be mutually exclusive. That’s not to say I’m a creationist either. Its just to say that we are humans making these judgements about weather or not we believe in god, etc., so there are the human limitations in our judgement abilities. We are not gods, for sake of this writing. Sure, in comparison to dogs and other lower forms, we may be gods (in case anyone wants to pick it apart and pull a fragment out of context.) I don’t think we’re supposed to know where we come from, at least not yet, and I think the one thing "god" wants is what I call "virgin information". That being new, unique data (i.e. what’s this specific individual going to do in this specific situation? type of thing.) Of course, I am a human making this judgement, at least, last time I checked!

[Tortoise]

Regarding Adam and Eve; my point was simply that it is a 'theory' that doesn't really hold much merit given the alternative theory of Darwinism which is much more believable and generally accepted to be true.

Yes, it was pointless and obscure. Sorry about that, but there are many threads on the topic of grapefruit juice already and every now and again a new one comes along which serves only to confuse. But I shouldn't have been so quick to diss your theory. Apologies.