Note that I am NOT advocating this or suggesting that anyone can safely use these amounts of APAP. This is for informational purposes only!
Also note that this is a pretty involved topic, there is a lot to read in this first post. Just thought I'd warn ya. First a quote from one of my own posts in another thread:
"
SWIM has read that it is possible to build a tolerance to the liver toxic effects of APAP. SWIM attributes the fact that he is still alive to that fact. At his worse, SWIM was taking 2+ grams of APAP in a single dose and 10+ grams of APAP in a 24 hour period regularly (sometimes seven days straight)."
...
"
SWIM has had his liver tested multiple times since then out of fear and it always comes back flawless. SWIM was very lucky. Also SWIM says the info about building a tolerance to the APAP says:
"Data suggests that some individuals who abuse very high doses of acetaminophen-containing hydrocodone products may be spared this liver toxicity if they have been chronically taking these products and have escalated their dose slowly over a long period of time."
from http://www.deadiversion.usdoj.gov/dr...ydrocodone.htm"
Now information on the LD50 of APAP varies wildly, but even considering that, one cannot deny that the amounts SWIM were ingesting were potentially toxic. SWIM did slowly titrate up his Hydrocodone/APAP use slowly over the course of a year. If this "tolerance" is indeed possible, I wonder why it occurs? I have a theory but I'd like some input. First a little primer on APAP toxicity for those who don't know how it occurs. I'll keep it brief, if you want to know more look it up on Wikipedia 
APAP by itself is not toxic. Your liver metabolizes it in two ways. The majority of it is turned into inactive non toxic substances and excreted harmlessly. A small amount is oxidized by the CYP450 system into a toxic metabolite, N-acetyl-p-benzo-quinone imine. With normal doses this substance is conjugated with glutathione and is thus excreted safely. With an APAP overdose, you basically use up the glutathione faster than you can make more, thus you run out and the conjugation cannot take place. This means the N-acetyl-p-benzo-quinone imine is left floating about your liver and causes harm. If enough damage is caused your liver fails etc. That's a crash course in APAP toxicity. Now on to my point about tolerance.
I'm no expert, I don't have any degrees in medicine, nor have I even consulted someone who does on this matter. I am just someone who is very interested in the medical field and specifically medications. How they work, why they work, what happens to them inside the body etc. are all topics I love to discuss. Therefore, this tidbit here we are discussing really piques my interests. I would however, like to say I have done countless amounts of research on all medical topics, so I'm not just randomly pulling stuff out of thin air either. Basically I'm trying to say that even though I have no formal training in this field, I still have a good sense of what's going on. But I can and do make mistakes and if I make one please feel free to correct me.That being said, on to my proposal for why this possible tolerance may occur.
There are two ways I think this could occur. The first and least likely in my opinion is that the liver somehow becomes "immunized" if you will. That it develops the ability to not be damaged by N-acetyl-p-benzo-quinone imine. Though possible in a rare way, I really doubt that is it. That's kinda like saying if I were to hit you with a hammer every day, eventually you will be unable to be hurt by hammers
. An amusing thought, but not too convincing. The only way I think it might work is if the body somehow learned to attack N-acetyl-p-benzo-quinone imine via the immune system. In our hammer analogy, this would be like you realizing that I'm gonna be coming at you with a hammer every day, so you realize you need to protect yourself and start wearing some armor. But I don't think N-acetyl-p-benzo-quinone imine can trigger an immune response on it's own. To my knowledge the only way chemicals can begin to trigger immune responses is if they are attached to a known pathogen that will (I could be wrong here). That's how the NicVAX (a nicotine vaccine) works(read about that here if you like
http://en.wikipedia.org/wiki/NicVAX). Now on to the reason that I think is the most likely culprit.
The body constantly makes glutathione as it is used up. I think this possible tolerance is caused by the liver adapting to the increasing need for glutathione and thus producing more of it, or producing it more rapidly. Thus it gains an increased capacity to metabolize N-acetyl-p-benzo-quinone imine. This would be a difficult effect to achieve because as far as I can see there are only a couple of ways to induce this adaptation
The first would be that you kept your glutathione levels consistently depleted over a period of time. I.E. keeping yourself in borderline APAP toxicity. That's not a very wise thing to do. The other, equally unwise way, and the way I would think induces it is based on the fact that the liver is an extremely resilient organ. Even with a decent sized APAP overdose, if you survive past the first four days or so, your liver pretty much heals itself and keeps right on going unless you've done major damage. So basically each time you push your liver to the limit, if it recovers it then adapts to the increased glutathione needs. So basically I'm saying it could be caused by slightly damaging your liver and then letting it recover, and this happening over and over again.
No matter how you look at it, APAP is pretty bad stuff. I'm sure my friend wished Hydrocodone was not almost always paired with some other pharmaceutical intended to cause you harm if you dare desire to feel good. Of course, that's the opinion of today's society. Feeling good is bad unless it happens spontaneously through no control of your own. Once again I'm not recommending you or your friends go and try to develop an APAP tolerance. So what does everyone think? Any other possible causes for the tolerance, or arguments against it, or proving me wrong or right or any comments at all are welcome!
22-03-2008, 20:36
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