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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 9 of 9. This is the beginning of the thread.
Posted by corafree on June 12, 2005, at 17:29:13
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?
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, cf
Posted by Larry Hoover on June 12, 2005, at 17:29:13
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
Posted by corafree on June 12, 2005, at 17:29:14
In reply to Re: Metabolization Question » corafree, posted by Larry Hoover on June 11, 2005, at 21:24:50
Tks Lar.
Just hit the wrong key and deleted my first response to your response.
To begin with, thanks for taking your time to explain; though don't understand why you gave examples ... assuming the metabolite was not active. That would mean the 2D6 enzyme was not active, right?
Am I correct in saying that a person cannot label themselves ALWAYS a 'poor metabolizer', 'normal metabolizer', or 'extensive metabolizer', ... because w/ one drug they may be a 'poor metabolizer', w/ another drug a 'normal metabolizer', and w/ another drug an 'extensive metabolizer'?
Lots of Tks, cf
Posted by Larry Hoover on June 12, 2005, at 17:29:14
In reply to Re: Metabolization Question » Larry Hoover, posted by corafree on June 12, 2005, at 0:59:29
> Tks Lar.
>
> Just hit the wrong key and deleted my first response to your response.
>
> To begin with, thanks for taking your time to explain; though don't understand why you gave examples ... assuming the metabolite was not active. That would mean the 2D6 enzyme was not active, right?2D6 is *the* enzyme usually involved in issues of poor to extensive metabolization of drugs. It is the only cytochrome enzyme that is not inducible. All the others can increase activity if their load increases. With 2D6, you get what God gave ya. In a fairly small sampling study I read, the 2D6 activity within a group was accurately measured. The variability within the group was 118-fold. That's 118 times, or 11,800% difference in metabolic rate between the poorest of the poor and the most extensive of the extensive metabolizers.
An active metabolite is a converted form of the parent drug that itself has activity. In the case of Paxil and 2D6, you'd be looking at desmethylparoxetine. If desmethylparoxetine also has pharmacological activity, then the drug's effects include both premetabolism and post-metabolism effects. The true limiting factor then becomes elimination (via urine or feces).
I gave two opposing examples. In the first instance a poor metabilizer had enhanced drug effects, whereas in the second example, the poor metabolizer had minimal drug effects. The extensive metabolizer, on the other hand, had minimal effects and maximal effects, respectively.
> Am I correct in saying that a person cannot label themselves ALWAYS a 'poor metabolizer', 'normal metabolizer', or 'extensive metabolizer', ... because w/ one drug they may be a 'poor metabolizer', w/ another drug a 'normal metabolizer', and w/ another drug an 'extensive metabolizer'?
As I say, this usually applies to 2D6 metabolism (I'm trying to simplify, and there are exceptions), and 2D6 activity is 100% genetically regulated (no environmental regulation of any sort; you get what you were born with). Therefore a poor metabolizer is a poor metabolizer of any drug that uses that same enzyme.
The effects, though, don't just depend on the enzyme activity alone. Another factor to consider is the relative potency of the parent drug compared to its metabolites. A poor metabolizer can have minimal drug effect, or maximal, depending on this latter factor.
> Lots of Tks, cf
My pleasure,
Lar
Posted by corafree on June 12, 2005, at 17:29:14
In reply to Re: Metabolization Question » corafree, posted by Larry Hoover on June 12, 2005, at 11:26:37
Do we know which drugs need 2D6 and which do not?
Can a person be tested for their 2D6 enzyme?
I now promise ... I won't ask another question!
This has been an eye-opening education.
Did I tell you, one time I took Zoloft, felt a big surge of energy and optimism for about an hour; then fell back into depression and never again felt that relief w/ Zoloft?
One time I ate some bright green cooked spinach and felt that same surge. I guess Popeye was a true story! I am anemic; have been even long after having elective removal of birthing organs. Finally forked out $ for liquid iron accompanied by B vites; not pleasant to swallow!
So much for weekend; apologize if your relaxation or fun was curtailed! Dr. Bob and all are lucky to have you here! (And, I very sincerely mean that.) cf
> > Tks Lar.
> >
> > Just hit the wrong key and deleted my first response to your response.
> >
> > To begin with, thanks for taking your time to explain; though don't understand why you gave examples ... assuming the metabolite was not active. That would mean the 2D6 enzyme was not active, right?
>
> 2D6 is *the* enzyme usually involved in issues of poor to extensive metabolization of drugs. It is the only cytochrome enzyme that is not inducible. All the others can increase activity if their load increases. With 2D6, you get what God gave ya. In a fairly small sampling study I read, the 2D6 activity within a group was accurately measured. The variability within the group was 118-fold. That's 118 times, or 11,800% difference in metabolic rate between the poorest of the poor and the most extensive of the extensive metabolizers.
>
> An active metabolite is a converted form of the parent drug that itself has activity. In the case of Paxil and 2D6, you'd be looking at desmethylparoxetine. If desmethylparoxetine also has pharmacological activity, then the drug's effects include both premetabolism and post-metabolism effects. The true limiting factor then becomes elimination (via urine or feces).
>
> I gave two opposing examples. In the first instance a poor metabilizer had enhanced drug effects, whereas in the second example, the poor metabolizer had minimal drug effects. The extensive metabolizer, on the other hand, had minimal effects and maximal effects, respectively.
>
> > Am I correct in saying that a person cannot label themselves ALWAYS a 'poor metabolizer', 'normal metabolizer', or 'extensive metabolizer', ... because w/ one drug they may be a 'poor metabolizer', w/ another drug a 'normal metabolizer', and w/ another drug an 'extensive metabolizer'?
>
> As I say, this usually applies to 2D6 metabolism (I'm trying to simplify, and there are exceptions), and 2D6 activity is 100% genetically regulated (no environmental regulation of any sort; you get what you were born with). Therefore a poor metabolizer is a poor metabolizer of any drug that uses that same enzyme.
>
> The effects, though, don't just depend on the enzyme activity alone. Another factor to consider is the relative potency of the parent drug compared to its metabolites. A poor metabolizer can have minimal drug effect, or maximal, depending on this latter factor.
>
> > Lots of Tks, cf
>
> My pleasure,
> Lar
Posted by Larry Hoover on June 12, 2005, at 17:59:09
In reply to Re: Metabolization Question » Larry Hoover, posted by corafree on June 12, 2005, at 14:49:04
> Do we know which drugs need 2D6 and which do not?
Yes. Modern drugs, without doubt. There are some others with some degree of poor/extensive variability, but 2D6 is the most critical, by far.
> Can a person be tested for their 2D6 enzyme?
Yes. Here is one example of a site where the tests are available:
http://www.wdxcyberstore.com/dnadrrepr.html> I now promise ... I won't ask another question!
Not necessary. I like questions.
> This has been an eye-opening education.
>
> Did I tell you, one time I took Zoloft, felt a big surge of energy and optimism for about an hour; then fell back into depression and never again felt that relief w/ Zoloft?That's quite unusual. I can't give you an explanation for that.
> One time I ate some bright green cooked spinach and felt that same surge. I guess Popeye was a true story! I am anemic; have been even long after having elective removal of birthing organs. Finally forked out $ for liquid iron accompanied by B vites; not pleasant to swallow!
Spinach is actually a poor source for iron, due to the high oxalate content. The iron is very poorly absorbed.
If you're anemic, take vitamin C. Your iron uptake is entirely dependent on vitamin C.
> So much for weekend; apologize if your relaxation or fun was curtailed! Dr. Bob and all are lucky to have you here! (And, I very sincerely mean that.) cfNo problem. I'm glad to assist.
Lar
Posted by Phillipa on June 12, 2005, at 21:26:27
In reply to Re: Metabolization Question » corafree, posted by Larry Hoover on June 12, 2005, at 17:59:09
Think I'm a poor metabolizer. Fondly, Phillipa
Posted by blondemomints on June 15, 2005, at 13:27:53
In reply to Re: Metabolization Question » corafree, posted by Larry Hoover on June 12, 2005, at 17:59:09
Larry,
You seem to be very knowledgable, a pleasure to read your posts. Do you have any knowledge of how a gastric bypass patient (myself, post-op 3 years) deals with the absorption/metabolization of meds? My dr says "we really don't know because there's not enough research".
Surely I can't be the only post-op patient having problems with depression, meds, etc.
Just curious if you know of any resources?
Thanks in advance!
God Bless
Posted by gardenergirl on June 15, 2005, at 23:06:23
In reply to Re: Metabolization......Hey Larry? What if...., posted by blondemomints on June 15, 2005, at 13:27:53
Hi,
Just wanted to let you know that Larry will not be able to post for approximately six weeks due to a block. I hope someone else can jump in to answer your question.gg
This is the end of the thread.
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