Amphetamine pharmacokinetics

[Dr. Beat]

I am finding it hard to find detailed infomation on amphetamine pharmacokinetics, like which enzymes break it down, and what the metabolites do?

 

[MattPsy]

Quite alot of amphetamine is excreted unchanged.

However, the main products of metabolism are 4-hydroxyamphetamine, alpha-hydroxy-amphetamine, and consequently 4-hydroxy-alpha-hydroxy-amphetamine. Both of these are active, but because they are much more polar they will find it much harder to cross the BBB to have any strong psychoactive effect.

It can then be deaminated to phenylacetone and then converted to benzoic acid...


IIRC it is CYP2D6 that does the hydroxyl additions. Not sure about the subsequent reactions.

I'm not overly informed on this side of psychoactives though (pharmacokinetics) so take the above with a pinch of salt . Bilzor and associates will be able to answer this better .

 

[Synapse999]

eh, i have shit bookmarked randomly everywhere..can't ever find anything heh.
guess it depends on what about it your looking into. from complex explaination or the long and short of it.


This here is a decent read on the technicals, easy to branch off from there.

http://www.clinchem.org/cgi/content/full/49/1/121

 

[bigmac74]

Don't forget monoamine oxidase, amphetamine is a monoamine.

 

[MattPsy]

IIRC the MAO's in the brain dont attack amphetamine or related compounds. The brain MAO's are different from say, the MAO's in the stomach.

5-HT, DA and the like I can understand since they are open to metabolic attack, like how N,N-DMT is inactive orally because a variant of MAO destroys it in the stomach, but when you add on say, an alpha methyl (making it AMT), the MAO's can't break it down in the stomach (guess that methyl protects it - if anyone has any information on how molecular modification affects enzyme attack suscepibillity it would be GREATLY appreciated), so it gets to your bloodstream and consequently your brain and 5-HT receptors... then you trip .

 

[MattPsy]

Here's a excerpt from the article Synape999 linked (nice reference, cheers for that, found it interesting !) for easier reading:

"METH is almost entirely (90%) eliminated in urine (9). In urine of pH 6–8, ~22% of a METH dose is excreted as unchanged drug, 15% as p-hydroxymethamphetamine (pOH-METH), 4–7% as amphetamine (AMP), and 1% as p-hydroxyamphetamine (pOH-AMP) (8)(9). Of quantitatively minor importance are phenylacetone and the hydroxylation products of AMP and pOH-AMP, i.e., norephedrine and p-hydroxynorephedrine (10). During phase two biotransformation, the majority of pOH-METH and pOH-AMP is conjugated with glucuronic acid (9). The renal excretion of METH and AMP is enhanced by urinary acidification, producing shortened plasma elimination half-lives and increased total clearance (11)."

 

[Helios.]

^^MattPsy brings home the Au here.

 

[hugo24]

I've read about the Phenylaceton metabolite.This might be a placebo effect but I think sometimes the sweat and pee smells a bit of Phenylaceton.But it could be Phenylacetic acid as well,this one smells in the smallest concentrations.And it is possible as a metabolite.

 

[Survival0200]

Weird there's no comprehensive information about (dex)amphetamine's pharmacokinetics at RxMed's Dexedrine(R) characteristics.

 

[hussness]

Anyone know anything about the toxicity of these metabolites?

 

[BilZ0r]

I give the answers here my rubber stamp of agreement.
The cyp2d6 ring hydroxylated metabolites should be less (neuro)toxic than their parent compounds, as they should have shitty brain permiability.

 

[hussness]

So here's a further extrapolation: Does MDMA's reputed toxicity have anything to do with methanol -> formaldehyde -> formic acid metabolism?

 

[/navarone/]

So here's a further extrapolation: Does MDMA's reputed toxicity have anything to do with methanol -> formaldehyde -> formic acid metabolism?

well i recently found out that SOME methamphetamine in the body gets broken down by N-dealkylation (which gives methanol and amphetamine), Deamination (which removes the amine and probably turns it into urea), and aromatic dehydroxylation (which attaches a OH on the 4th carbon).

I'm pretty sure MDMA goes through N-dealkylation and deamination as well becuase the enzymes have a regional affinity so the methylene dioxy shouldn't bother, but its skips the aromatic dehydroxylation becuz it obviously has already 2 oxygens on the aromatic ring. I read though that the methylene dioxy ring of MDMA and MDA gets attacked by an enzyme which removes the carbon (and maybe turns it into methanol..not sure) resulting in 2 hydroxides on the 3rd and 4th carbon (like dopamine).
Of course not all MDMA molecules get metabolized fully and i think a few escape the body unchanged....but i can't be sure wihtout a reference.

Based on what i read, if a MDMA molecule undergoes all the steps of its metabolism the resulting molecule SHOULD be:

3,4-Dihydroxy-phenyl-1-propan-2-ol (which sounds a bit nasty to me)

and:

4-hydroxy-phenyl-1-propan-2-ol (in the case of amphetamine IF fully metabolized)

I'm not sure but if the above molecule or a previous metabolite of it has an affinity for the enzyme 'Tyrosine hydroxylase' a second OH would add on the 3rd carbon.

I'm not aware of any further metabolic steps.

 

[/navarone/]

BTW the ammount of methanol produced by metabolism of meth and MDMA is really small, especially becuz not all molecules are metabolized.

From the article i read N-dealkylation takes place in the liver, but im afraid if this process also takes place in the brain which is more fragile and less methanol tollerant than the liver.
Is it possible that N-dealkylation could take place in the brain?

 

[Helios.]

Yeah, that's what I'm thinking.

 

[hugo24]

Yeah we have to consider metabolisation in the brain.And then there are the metabolites formed in the brain who can't get back out easily through the BBB.

Point 2, do we know dealkylation leads to alkylol? Theres much emphasis in literature on the other side of the breakup.

 

[Helios.]

EtOH definitely gets in the brain, but back to AMP metabolism, phenylmethylenealphapiperidines (PMAPs) don't have this problem.

Ritalin/methylphenidate does, due to its Bz-(CO2Me)-R group, but it's not a strict PMAP.

EtOH --> CH3CO2H.
Bz-(CO2Me)-R --> Bz-(CO2-)-R + MeOH.
MeOH --> HCO2H.

 

[Helios.]

As for the alkylol point, what is the alternative? Glucuronates?

 

[bigmac74]

IIRC the MAO's in the brain dont attack amphetamine or related compounds. The brain MAO's are different from say, the MAO's in the stomach.

Well i'm pretty sure that MDMA (an amphetamine) is broken down by MAO in the brain, as one of the neurotoxicity theories is down to an MDMA metabolite, and the fact that selegeline - an MAO-B inhibitor - prevents MDMA induced neurotoxicity, which proves something at least.... [1], [2] & [3].

 

[hussness]

3,4-Dihydroxy-phenyl-1-propan-2-ol (which sounds a bit nasty to me).

What about that sounds nasty? I would think the lipophobicity of that compound would make it a relatively safe metabolite since it would have almost zero brain penetration. I wouldn't be surprised if phenylephrine has that as a metabolite.