Posted by Larry Hoover on June 11, 2005, at 21:24:50 [reposted on June 12, 2005, at 17:29:13 | original URL]
In reply to Metabolization Question, posted by corafree on June 11, 2005, at 17:23:07
> Thinkin' about poor and extensive metabolizers, or, poor/slow, and extensive/normal/fast metabolizers; two groups, the first w/ the two descriptive words of poor and slow, and the second w/ three descriptive words of extensive, normal, fast. Isn't this correct? Anyone? Doesn't the above lanquage pretty much throw you into the first or second group?
I'd make three groups. Set normal at some arbitrary average rate, defined at 100%. Poor metabolizers would be, say, at 50% or less. Extensive metabolizers could be 200% or 300% or more. It's a continuum, with some instances of 0% rate (but that's pretty rare).
> The way I had thought I understood it was as follows:
>
> An extensive/normal/fast metabolizer carries an agent in their body more readily (feeling effects more quickly) and has a longer period of availability (sustaining the effect for a longer period of time), THAN a poor/slow metabolizer.
>
> If the above is correct, a poor/slow metabolizer NEEDS MORE medication or doses.
>
> Am I looking at this backwards?
>
> I had posted about this long ago and tried to search for it, but couldn't find, and my memory is playing tricks on me!
>
> Now, can someone tell me, am I looking at this backwards? I realize I am looking at it simplistically!
>
> Thanks anyone, cfNot backwards. You've mixed up the attributes a little. It depends on the nature of the drug, as well as the effect of the rate.
Some drugs are active in their ingested form. They don't need to be metabolized to become active. Metabolizing them inactivates them (in this simplest case).
Other drugs are swallowed in an inactive form, and metabolizing them activates them. The effect of poor/extensive metabolizer rates is the opposite in each case.
For an example of the first situation, let's consider the antidepressant Paxil (paroxetine). It's primary metabolic route is via the enzyme 2D6, an enzyme which exhibits this poor/normal/extensive metabolic rate. And let's assume that the metabolite is no longer active in any way.
Poor metabolizers would only very gradually break the Paxil down, so their blood concentration would stay higher longer than any other rate group. They would have the most profound drug effects at a given dose. The normal group would be right up the middle; these are the folks the dose tables were developed around. The extensive metabolizers would burn up the Paxil very quickly, and would show a pronounced drop in blood concentration between doses. They would also have trouble building up any sustained drug effect.
In the second situation, let's consider the drug codeine, if used for pain. It's almost totally useless in its original state for that purpose, but that same enzyme, 2D6, desmethylates it to morphine. That's what makes it useful for pain relief. Again, let's consider the different rate groups.
The poor metabolizers would get the side effects of codeine (e.g. constipation), but get little or no pain relief, as they cannot convert it to morphine. Normal metabolizers get steady slow conversion of codeine to morphine over a few hours, and thus mild to moderate analgesia. Extensive metabolizers, however, get a rapid rush of morphine, with the primary effects being psychoactive/euphoric.
Note that these rate effects are independent of uptake from the gut. The rapidity of onset of effects, though, can differ substantially in the different groups due to the differences in conversion of the parent drug to inactive (or active) metabolites. I didn't even get into the effect of active metabolites here, to keep it simple. And drugs that have multiple routes of metabolism also can have unusual effects in some individuals due to differences in the relative rates of each of the enzymes in question.
I hope this clears up your confusion, but if not, ask me questions.
Lar
poster:Larry Hoover
thread:511635
URL: http://www.dr-bob.org/babble/20050611/msgs/511636.html