inhibiting the enzyme that metabolises cocaine

[ribbit]

Hey BL! I was wondering if any resident knew what to take to inhibit the breakdown of cocaine in the gut, thus making it orally active. I already know of coca-ethanol, but I dislike the alcohol and the toxicity of the combination. I have a hunch taking an maoi (b) would work, but have nothing on paper thus proving my hypothesis. Thank you!

 

[titstypedthis]

maoi would be bad


like really bad brah

 

[Iodjini_dk]

I dont know a lot about biochemistry. But in general it can be very dangerous inhibiting your own metabolic enzymes. Especially when doing so to potentiate a drug. Ayahuasca is generally not a motiv that can be used with regards to other drugs.

 

[Vader]

Cocaine is not a monoamine, MAOI wouldn't work.

 

[ribbit]

I've heard of locals mixing caapi leaves with coca leaves inside ayahuasca brews. if it's not mao then what enzyme is responsible for it's poor bio-availability in the body and how can we inhibit it! I don't think it's grapefruit juice...

 

[Vader]

I think it's that the acidity of the stomach causes hydrolysis of the ester, rather than the action of enzymes, that is responsible for the inefficiency of oral administration. You could eat a lot of antacid, that should increase the efficacy.

 

[Hyperthesis]

Cocaine is not a monoamine, MAOI wouldn't work.

The tropane-ring contains a tertiary amine and is therefore a potential MAOI-substrate. It doesn't matter this much if the compound is 'monoamine' or not. This classification is purely man-made and has only limitied validity in natural systems. The relevant databases list primary, secondary and tertiary amines altogether as being substrates of MAO.

Nonetheless, the main metabolic fate of cocaine is decided by a couple of esterases (EC 3.1.1.8 and .8), which cleave it into benzoylecgonine and ecgonine methylester. The main responsible are (ChE = choline esterase):

* human ChE1 (hChE1)
* intestinal ChE (hChE2 or iChE)
* serum butyrylcholinesterase (hBuChE, "plasma cholinesterase")​

Intestinal CE and hBuChE hydrolyze the larger benzoyl ester linkage on cocaine, only hCE1 hydrolyzes the methyl ester linkage to generate benzoylecgonine. These 3 enzymes account for ca. 95% of cocaine's metabolism, hBuChE

N-Demethylation is performed by CYP450-type enzymes in the liver, yielding the active metabolite norcocaine. This equals actually MAO-activity, but as mentioned above is this only a minor pathway.


Inhibition of hBuChE was described several times in the literature, see e.g. BRENDA (http://www.brenda-enzymes.org/), search for EC 3.1.1.8 and then restrict the results to species Homo sapiens. Some examples for hBuChE-inhibitors:

* debromoflustramine B
* (2x)-1,4:3,6-dianhydro-2-O-(benzylcarbamoyl)-5-O-([[(2E)-3-phenylprop-2-enoyl]oxy]carbonyl)-D-arabino-hexitol
* (2xi)-1,4:3,6-dianhydro-2-O-(benzylcarbamoyl)-5-O-(phenoxycarbonyl)-D-arabino-hexitol
* (4-([benzyl-(2-dimethylaminoethyl)amino]methyl)-phenyl)-(3,4-dimethoxyphenyl)methanone
* 1,1'-(benzene-1,3-diyldimethanediyl)dipyridinium dibromide
* 10-(2,2-dimethylpropanoyl)-10H-phenothiazine
...​

The list is actually very long, check it out on your own.

I can only strongly discourage to experiment with any of these inhibitors. If the selectivity over other choline esterases is not high enough it gets quickyl lethal.
Even a highly selective inhibitor would not be safe; hBuChE has some important functions to fulfill and its inhibition would get nasty.



P.S. And cocaine is actually quite active when taken orally!!! Bioavailability intranasal vs. oral is comparable (search this forum; exactly this topic was discussed before), but the oral route lacks of course the rush and is therefore considered pointless by most users.

 

[ribbit]

Thanks Hyperthesis! I don't think I'll mess around with any inhibitors, but maybe competitors of the enzymes or find synergistic combinations with the coca leaf, I have found Maeng da Kratom is perfect at this. Would there be any potential dangers of mixing say a reversible maoi of the b variety with the effects of cocaine? Cocaine prevents the re-uptake of dopamine, and maoi(b) delays the breakdown of lingering dopamine inside the body, so I can see an inhibitor increasing the intensity through this action, but would there be any large risk of too much dopa building up? I would probably attempt the same with a maoi(a) as well, seeing as cocaine also is a serotonin re-uptake inhibitor, any risk of serotonin syndrome?

Thank you very much, I can post first hand experiences of such ideas as soon as I verify I wont kill myself with a 5 gram batch of coca tea.

 

[Hyperthesis]

Personally, I would NEVER encourage experimenting with ANY enzyme inhibitor unless there is a clear medical indication. I can't claim to be an expert in this field and side-effects - potentially lethal ones! - are unforeseeable.

I can not recommend to do this with a clear conscience. You are venturing into really dangerous territory, ribbit, but that are just my 2 cent on this topic...

 

[nuke]

answered