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Messing with drug metabolism beyond the CYPs

N

nj754

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Jun 14, 2011
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The potential for causing beneficial drug interactions via the cytochrome P450 (CYP) system is pretty well-trod territory. For the few recreational drugs that can be potentiated this way, you can basically do a quick search on PubMed or find a book in a medical library that will tell you what you need to know. The ones you can pull off with OTC substances are especially well-known. The CYP system is only one set of enzymes that are important in drug metabolism, however. A lot of drugs are activated or inactivated by conjugation with glucuronic acid by an entirely different system of enzymes called UGTs. It seems that the scientific community is just now exploring this system in detail. In my humble opinion, there is a lot of potential here for potentiating recreational drugs. If you could figure out how to inhibit UGT1A3 and UGT2B7, for instance, you could block the metabolism of hydromorphone. If you could selectively block UGT1A3, which makes the undesirable metabolite of morphine, you could possibly enhance morphine quite a bit. Preventing the glucuronidation of morphine could also potentially significantly elevate the amount of bioavailable morphine that's produced from a dose of codeine. This approach to enhancing codeine is a lot more promising than anything you can do with CYPs alone, IMHO.

Here is an interesting article on UGTs and opioids: http://psy.psychiatryonline.org/cgi/content/full/44/2/167

There are other enzymes that are important in metabolizing recreational drugs. Cocaine is metabolized primarily by butyrylcholinesterase (BChE). The wide distribution of BChE in the body is apparently the reason cocaine has such a short half-life. A couple of alzheimers drugs do a good job of inhibiting BChE, but at the cost of being prescription-only and also inhibiting AChE. AChE inhibition in the brain could theoretically increase the risk of seizure, which is not what you want with cocaine. However, there are specific BChE inhibitors, and ones that don't cross the BBB. There is a good chance that some are cheap, safe, and OTC.
 
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That is a nice table. It's interesting that ketoconazole is a 2B7 inhibitor. I took it and itraconazole with oxycodone and it definitely seemed to boost the effect.
 
I'm too lazy to do the exact math right now, but if the glucuronyl transferases generate equal amounts of M6G and M3G, and if M6G is ten times the potency of morphine, and if M6G has a half life comparable to morphine's, it's probably counterproductive to inhibit the enzyme. Does this makes sense? I'm on Xanax and I just went running.

ketoconazole lowers testosterone levels, so if you're male it's probably not something to take with gusto
 
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235360287471352662 said:
I'm too lazy to do the exact math right now, but if the glucuronyl transferases generate equal amounts of M6G and M3G, and if M6G is ten times the potency of morphine, and if M6G has a half life comparable to morphine's, it's probably counterproductive to inhibit the enzyme. Does this makes sense? I'm on Xanax and I just went running.
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That would be true if you had to inhibit them all at the same time. According to the article I posted, UGT2B7 is primarily responsible for M6G, and UGT1A3 is primarily responsible for the inactive M3G. If you could selectively block UGT1A3, you could potentially produce a lot more M6G.

According to the link you posted, diphenhydramine and promethazine are substrates for UGT1A3, so they may also be competitive inhibitors. This could be the real reason that some antihistamines seem to potentiate opiates. If you know exactly which enzymes they inhibit and by how much, you can make a more rational choice of potentiator for a given opiate.

ketoconazole lowers testosterone levels, so if you're male it's probably not something to take with gusto
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Who needs testosterone when you have opioids?
 
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lethe_drowned said:
Fluconazole is a over the counter UGT2B7 inhibitor, does that help? it's used for treatment of thrush!

from what i can tell it does inhibit M6G though. i am howeve no expert. try these sites: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=42248
: this one needs down loading: http://www.docstoc.com/docs/69786509/UDP-GLUCURONOSYLTRANSFERASE-2B7-_UGT2B7_-UTILISES-BOTH-UDP-
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There is no systemic azole antifungal that is OTC in the US that I'm aware of. You can get them as creams, if you want to eat that. My previous research led me to ketoconazole, itraconazole, and voriconazole as good potentiators, not fluconazole. But I couldn't tell you the reason off the top of my head.
 
sorry i'm in the uk, and it's still pharmacy only (in one time capsule) . fluconazole might not be the best example but here its the only UGT2B7 you can get ove the counter that i know of. this sounds like it could be promising though we should have a word with a mod an see if we can get some attention ( maybe get it moved to a potentiators thread) someone must have some experiance with this. what about Dexamethasone it's a corticosteroid i know it's over the counter here in some creames??? sorry i'm a bit out of my depth here.
 
lethe_drowned said:
sorry i'm in the uk, and it's still pharmacy only (in one time capsule) . fluconazole might not be the best example but here its the only UGT2B7 you can get ove the counter that i know of. this sounds like it could be promising though we should have a word with a mod an see if we can get some attention ( maybe get it moved to a potentiators thread) someone must have some experiance with this. what about Dexamethasone it's a corticosteroid i know it's over the counter here in some creames??? sorry i'm a bit out of my depth here.
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I'd rather not do anything like eat a cream. I also tend to frown on messing too much with my hormones. A little bit of dexamethasone might not do any harm, but I am looking for drugs that are as safe and side effect-free as possible.

By the way, my interest in this is sparked a lot by the fact that I live near the Mexican border, so I can cross over and easily buy most non-controlled prescription drugs. In some cases, even controlled ones, but they tend to cost a lot more and present a problem when crossing back into the US. If you invest some effort, a lot of prescription drugs can be ordered off the web, although I haven't tried it myself.
 
Very interesting, I don't have anything to contribute yet because I'm wrapped up in my amphetamine thread. But, keep up the good work!
 
I've been thinking about the metabolism of morphine and the insane duration pod tea for some time. Always knew it was down to enzyme saturation, so I presume that many of the other opium alkaloids are also metabolised heavily by UGT enzymes. And the fact that grapfruit juice is an excellent potentiator suggests that many of them must also be metabolised by CYP3A4, and with that enzyme out of the picture, the UGT enzymes must be saturated much quicker.

Since I don't have access to any decent opiates and kratom just isn't worth the hastle, I'd be interested in other ways to potentiate morphine (and codeine) from pods as much as possible without potentiating the other alkaloids. It seems like a UGT1A3 inhibition would be the way forward whilst leaving 2B7 alone (possibly even induced? depends on M6G's recreational potential I guess). More of the parent morphine overall, more M6G, less toxic M3G and the other alkaloids free to be dealt with by P450 enzymes as much as possible.

It just seems there's not enough known about inhibitors/inducers of these enzymes. All the ones you guys have been mentioned don't sound like they'd be worth it considering the potential for unwanted side effects and lack of information on the desired effects (enzyme inhition/induction).

I'll definately look into it more though. A fairly selective UGT1A3 Inhibitor would be interesting to try alongside pods.
 
If you like opiate/benzo combinations, temazepam seems to be a UGT1A3 Inhibitor (http://www.springerlink.com/content/r317512906642k79/). But I don't fancy trying Amitriptyline as a potentiator.

I found this interesting too: http://www.mdpi.com/1420-3049/15/5/3578/pdf
Seems Andrographis Paniculata (http://en.wikipedia.org/wiki/Andrographis_paniculata) extracts are good inhibitors of an array of UGT enzymes. Although how this would affect the other alkaloids in poppy pods I don't know. Its an interesting plant either way...

This looks like it'll be a good read to some people, I just don't have the time or focus right now: http://dmd.aspetjournals.org/content/26/6/507.full.pdf


And to the person who mentioned Diphenhydramine as a competitive inhibitor, do you have any other information or sources on diphen metabolism? I always assumed it was mostly cleared out by CYP2D6, a bit by 3A4, but heard/read nothing about UGT's. Diphen could be counter productive in my case (pods) as I'd be limiting codiene (codiene itch is horrific, and anti-histamines barely touch it) conversion and keeping the unwanted alkaloids around longer.
I should also note that I've never tried Diphen as a potentiator, or at all in fact. I've always used Etizolam rather than OTC sleeping aids and I've been happy with Cetirizine and/or Loratodine to take the edge of the poppy itch, although they only do so much, what with codeine and morphine being the itchiest things I can think of... And I suffer from prickly heat. This is my least favourite time of the year :(
 
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i don't know how easy it is to get Amitriptyline where you are (or in mexico) but there have been some studys with it ( it's a tricyclic anti-depressant) that show that through ugt1A3 and NBUP glucuronidation inhibition there was a decrease in the metabolic clearance of buprenorphien in the liver which lead to an "increase in negative effects for the dose" respitory depression ect. i can't find much on the internet to back this up but i'm sure if you look around you'll find somthing.
also doesnt temazepam potentiat through ugh2b7 inhibiton?
 
amitrytriptyline is a pretty heavy drug. Seriously, have you ever done it? The sedation alone may make it useless for potentiation, but there are numerous other effects to it.

It is certainly my favorite antidepressant (yes), but it's not something to be taken carelessly.
 
i've never taken it, in fact i don't know anyone that has i'm just looking for UGT inhbitors that don't affect M6G. it's a bit tricky though. another one would be oxazepam. they all seem to be prescription only and stuff you wouldent want to really take if you could help it (like nappy rash creams) i'd do love a cream tea but i'm not sure about how Hexadrol would do insted of yeo vally single?
the two benzo's i've stated might be good but they don't fit the OTC or easy to get bill.
 
I think this thread has been successful in shaking loose a bunch of useful ideas for drug potentiation. I am definitely going to look this up the next time I have the chance to dabble in opioids. I also posted some ideas on this other thread:

http://www.bluelight.ru/vb/showthread.php?t=581361

I like the idea of using quinine in tonic water to potentiate oxycodone. It's so simple and easy, and it apparently inhibits both 3A4 and 2D6.
 
I will say playing with drug metabolism factors is really fun. I don't know too much about it beyond CYPs but I will say for my self CYP is a HUGE factor. It may be random but I was on prozac 20mg for a while and it COMPLETELY inhibited the metabolism of codeine as I expected and it spiked plasma levels of dextroamphetamine and methylphenidate to dangerous levels. My doctors didn't believe me tell I showed them the research! Crazy stuff! Anyways..

The fluconazole topic is very real thing...lol my dad had to take it and I guess he couldn't sleep so he took a Xanax with it and he basically told me he was going to bed because he felt like he got hit with a hammer! Not to mention he takes a mild dose of OxyContin! Interesting! One of the more basic things I've noticed with my self is Hydrocodone with diphenhydramine...if I take diphenhydramine 12.5-25mg with 5-15mg of hydrocodone it shortens the duration of it to 2-3 hours with strong euphoria and sedation. I read about it and tried it and I remember getting insane euphoria! I literally as I was nodding mildly was thinking "How can I have this much euphoria!?!!". I'm definately not opioid tolerant or naive as I take them prn for pain but still it felt like the first time I took a Lortab 10 followed by a lortab 5 but better!

Also as sort of a warning...easy with the glucosteroids...go ahead try it but don't go crazy with the dosing or mix them with NSAIDs...
 
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