various dxm/dxo questions

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Echo - 17 Jul 2003 19:35 GMT

There are various documents pertaining to this ratio. One document
states that the typical ratio is 3:1, that is 3 times the amount of
dextromethorphan to dextrorphan, and yet another reliable source
argues that a majority of dextromethorphan is turned into dextrorphan
on its first pass through the liver. Does anyone know who is correct?
This is all assuming that the user is an extensive metaboliser. Also
is there a way to induce the P450-2D6 enzyme to turn dxm into dxo at a
faster rate without interfering with either of the drugs?

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Eric Wilk - 18 Jul 2003 03:00 GMT

> There are various documents pertaining to this ratio. One document
> states that the typical ratio is 3:1, that is 3 times the amount of
> dextromethorphan to dextrorphan, and yet another reliable source
> argues that a majority of dextromethorphan is turned into dextrorphan
> on its first pass through the liver. Does anyone know who is correct?

Well, at least how I understand it (from what I've read; sorry I'm not
citing stuff, but this is from my notes -- tell me if you need
ref's....)

DXM is metabolized into D-methoxymorphinane and D-hydroxmorphinane,
too, but only at a rate of about 15%. The ratio drug:metabolite in
urine (I'm pretty sure it's almost all excreted in this way, but I
could be wrong) after about 8 hrs is usually anywhere from 0:100 (all
metabolized) to 11:100. This would depend on the person; different
people have different genetics that encode for the enzyme which effect
its activity, and would also depend on the dosage, so it's hard if not
impossible to give an exact number, but 3:1 sounds like way too much
unmetabolized drug. Enzyme activity is thought to operate on a
diphasic Michaelis-Menten model -- I have a Vmax written of
10.5(+/-)6.1 nMol/min/nMol CYP enzyme in pig liver and Km =
6.9(+/-)3.6 uM. There is a first-pass metabolism by the liver by
demethylation via CYP.

> This is all assuming that the user is an extensive metaboliser. Also
> is there a way to induce the P450-2D6 enzyme to turn dxm into dxo at a
> faster rate without interfering with either of the drugs?

If the user is a good metabolizer it'll probably be mostly metabolized
in ~ 8 hours. As for the rate -- ??? I don't think any drugs have
been developed for this, yet (there is reason for study, however, as
this class of enzyme is really good at detoxifying lipophillic
substances.) There are drugs that do the reverse, however, that
inhibit the enzyme.

-- Eric

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