It's well known that oxycodone is converted to oxymorphone in the liver by CYP2D6. Research has been done to determine whether this process is important to the analgesic effect, using, for instance, subjects with varying levels of CYP2D6 activity, and these studies have found that oxymorphone did not significantly contribute to the analgesia. Hydrocodone is likewise metabolized to hydromorphone, and it was suggested that hydrocodone could be a prodrug, but, again, studies showed that hydromorphone did not make a significant contribution to the analgesia. It's tempting to think that there must be some way to unlock the potential of this conversion, seeing as how oxymorphone is about 10x more powerful than oxycodone when taken parenterally. CYP2D6 is very hard to induce, but it is quite possible to inhibit CYP3A4, which is the primary metabolic pathway for inactivating oxycodone, which would result in more oxycodone going the 2D6 route. However, once again, studies have been done, showing that, although you can alter the pharmacokinetics of oxycodone, oxymorphone levels still remain stubbornly low.
I have never come across an explanation in the literature for why oxymorphone levels are so resistant to being raised by metabolic processes. Then, finally, I realized the likely reason. Oxymorphone is very susceptible to first-pass metabolism in the liver; this is why oral bioavailability is on the order of 10%. So, as oxymorphone is being created in the liver, it is probably being metabolized there just as fast. Having oxymorphone be created in your liver is probably more like taking it orally, rather than parenterally, i.e. you lose 90% before it enters the bloodstream. Blocking CYP3A4 spares a little bit from being converted into noroxymorphone, but by far the most important metabolic pathway by which oxymorphone is inactivated is glucuronidation. Inhibitors and inducers of glucuronidation enzymes appear to be an active field of research, and although it may be feasible to inhibit the glucuronidation of oxymorphone, I have not been able to find many papers delving into this subject.
So, what I take from this is the lesson that, if you are trying to boost the effects of oxycodone, you might as well inhibit CYP2D6 as well as CYP3A4. Leaving CYP2D6 open to produce more oxymorphone may sound like a good idea, but it is a chimera. You will never achieve high enough levels of oxymorphone to outweigh the oxycodone that you are giving up. This likely applies even for inducing CYP2D6, if you can actually find a way to do this. I think the same logic applies as well to hydrocodone -> hydromorphone. The reason that there are reports that you can successfully increase codeine -> morphine by inducing CYP2D6 is most likely because codeine itself is inactive, so any morphine you can produce is basically free.
I came across this article just now, which is absolutely perfect for this topic. I haven't read it yet, so for all I know, it could cover everything I just said:
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2010.00673.x/pdf
I have never come across an explanation in the literature for why oxymorphone levels are so resistant to being raised by metabolic processes. Then, finally, I realized the likely reason. Oxymorphone is very susceptible to first-pass metabolism in the liver; this is why oral bioavailability is on the order of 10%. So, as oxymorphone is being created in the liver, it is probably being metabolized there just as fast. Having oxymorphone be created in your liver is probably more like taking it orally, rather than parenterally, i.e. you lose 90% before it enters the bloodstream. Blocking CYP3A4 spares a little bit from being converted into noroxymorphone, but by far the most important metabolic pathway by which oxymorphone is inactivated is glucuronidation. Inhibitors and inducers of glucuronidation enzymes appear to be an active field of research, and although it may be feasible to inhibit the glucuronidation of oxymorphone, I have not been able to find many papers delving into this subject.
So, what I take from this is the lesson that, if you are trying to boost the effects of oxycodone, you might as well inhibit CYP2D6 as well as CYP3A4. Leaving CYP2D6 open to produce more oxymorphone may sound like a good idea, but it is a chimera. You will never achieve high enough levels of oxymorphone to outweigh the oxycodone that you are giving up. This likely applies even for inducing CYP2D6, if you can actually find a way to do this. I think the same logic applies as well to hydrocodone -> hydromorphone. The reason that there are reports that you can successfully increase codeine -> morphine by inducing CYP2D6 is most likely because codeine itself is inactive, so any morphine you can produce is basically free.
I came across this article just now, which is absolutely perfect for this topic. I haven't read it yet, so for all I know, it could cover everything I just said:
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2010.00673.x/pdf
