Messing with drug metabolism beyond the CYPs

[nj754]

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.

The ideal would be to find something without side effects. When I take certain benzos, like Xanax, with any euphoric drug, it kills a lot of the euphoria.

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 speculated that diphenhydramine could be a competitive inhibitor of UGT1A3, since it's listed as a substrate on this page: http://www.pharmacologyweekly.com/c...medications-herbs-substrate-inhibitor-inducer

I didn't really get to investigating the suggestions and links you posted, but it's good to have them on the thread to look up when opportunity knocks.

 

[nj754]

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..

Do you have any idea what fraction of d-amphetamine gets metabolized and by which enzymes? Apparently some is made into p-hydroxyamphetamine by CYP2D6, but I've had a curiously hard time finding out how important this is. I was under the impression that it wasn't significantly metabolized.

 

[lethe_drowned]

this one's pretty strait forward, diclofenac potassium was shown in a study to inhibit glucuronidation of codeine. the study also says that it showed no use as a spring board of codeines analgesic effects.

 

[23536]

(I thought diphenhydramine was synergistic because of additive CNS effects)

I wish these threads came with numbers and graphics. Every substrate can be a competitive inhibitor, right?

(unless one drug has a much higher affinity to the enzyme than the other drug, or one drug is an irreversible inhibitor)

But unless you know at what dose the enzymatic process is saturated, you may just be shoveling dirt into the Grand Canyon.

Maybe at some point, the rate limiting step is the availability of glucuronic acid instead.

Also, for codeine, don't you want to enhance CYP2D6 instead of inhibiting it? For DXM too. Actually, for many prodrugs.

 

[itsok]

lethe - I found this about amitryptaline and bupe

The results suggest that both buprenorphine and amitriptyline moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.
- Eur J Clin Pharmacol 1987;33(2):139-46 -- Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers. -- Saarialho-Kere U, Mattila MJ, Paloheimo M, Seppala T.

http://www.personalhealthzone.com/drug_interactions/buprenorphine.html

 

[nj754]

(I thought diphenhydramine was synergistic because of additive CNS effects)

That's what most people thought, but isn't there something odd about how no one gets off on the effects of diphenhydramine itself, but when added to opioids, it suddenly becomes a big winner? Sort of like 1 + 1 = 3.

I wish these threads came with numbers and graphics. Every substrate can be a competitive inhibitor, right?

(unless one drug has a much higher affinity to the enzyme than the other drug, or one drug is an irreversible inhibitor)

But unless you know at what dose the enzymatic process is saturated, you may just be shoveling dirt into the Grand Canyon.

Every substrate probably has the potential to be a competitive inhibitor, but some make better inhibitors than others. How big the difference is from best to worst, I don't know. I just read the drug labels and some of the pharmacology papers. I'm not formally trained in this.

Maybe at some point, the rate limiting step is the availability of glucuronic acid instead.

Glucuronic acid is simply a glucose molecule that's been slightly oxidized, so, I doubt you would run out of it, unless perhaps you were on the ketogenic "starvation" diet.

Also, for codeine, don't you want to enhance CYP2D6 instead of inhibiting it? For DXM too. Actually, for many prodrugs.

Codeine is now believed to be (not sure if this is 100% certain) activated by conversion to codeine-6-glucuronide by UGT2B7. Here is a graphic I copied from the oxycodone thread (with improvements):

1.          UGT2B7
codeine ------------> C6G :)
            ~80%

2.          CYP2D6
codeine ------------> morphine :D
            <5%

3.          UGT1A3
morphine ------------> M3G :(
            >50%?

4.          UGT2B7
morphine ------------> M6G :D
            <50%?

Notice that C6G has a smiley face, but morphine and M6G have big smilies. There is apparently no good way to induce CYP2D6, short of the mythical glutethimide, but you could "enhance" its action on codeine by blocking reaction #1 and making more parent drug available for #2.

If you want to read the rest of my thoughts on this, you might as well go direct to the source: http://www.bluelight.ru/vb/showpost.php?p=9800378&postcount=3

 

[nj754]

this one's pretty strait forward, diclofenac potassium was shown in a study to inhibit glucuronidation of codeine. the study also says that it showed no use as a spring board of codeines analgesic effects.

That argues that maybe it's a waste of time trying to potentiate codeine by inihibiting both glucuronidation pathways -- unless diclofenac also inhibits CYP2D6. Here's a chart I found that seems to show that diclofenac has particularly high affinity for UGT2B7 and UGT1A3, the two UGTs that are significant in codeine's metabolism. Diclofenac is "D": http://dmd.aspetjournals.org/content/33/7/1027/F3.large.jpg

 

[nj754]

lethe - I found this about amitryptaline and bupe

The results suggest that both buprenorphine and amitriptyline moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.
- Eur J Clin Pharmacol 1987;33(2):139-46 -- Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers. -- Saarialho-Kere U, Mattila MJ, Paloheimo M, Seppala T.

http://www.personalhealthzone.com/drug_interactions/buprenorphine.html

Unless I'm missing something, buprenorphine seems like it would be an especially poor target for enhancement, because of the ceiling effect.

 

[lethe_drowned]

that's pretty interesting i though it was a safe bet that if a potentate increased respiratory depression then it would increase therapeutic effects as well. it's also interesting to know that Diltiazem could be use in overdoses with things like bupe, this has always been something i wanted to look into because if you OD on suboxone you'd be i trouble because of bupe/nalaxones high receptor affinity. thanks

sorry if this makes no sense it was aimed at the last post on the 1st page

 

[avcpl]

There is apparently no good way to induce CYP2D6, short of the mythical glutethimide, but you could "enhance" its action on codeine by blocking reaction #1 and making more parent drug available for #2.

I've found inconsistent info on 2D6 induction, but this chart has some listed, and includes ethanol: http://www.ildcare.eu/Downloads/artseninfo/CYP450_drug_interactions.pdf

I have to say that in my experience a small amount of ethanol does seem to do the trick, in the cases of inducing 2D6 for tramadol to M1 and hydrocodone to hydromorphone...

 

[Coolwhip]

I also tend to frown on messing too much with my hormones.

What do you think opiates do?

 

[Coolwhip]

Notice that C6G has a smiley face, but morphine and M6G have big smilies. There is apparently no good way to induce CYP2D6, short of the mythical glutethimide, but you could "enhance" its action on codeine by blocking reaction #1 and making more parent drug available for #2.

And by doing so you would be stopping the morphine from then being converted to M6G. You aren't going to get anywhere with codeine other than inducing CYP2D6. Unless your 2B7 inhibitor had an extremely short half-life.

I think time would be better spent figuring out how to increase hydrocodone -> hydromorphone, and oxyC -> oxyM. And preventing elimination through glucuronidation.

Selective 1A3 inhibition seems to be the most useful.

 

[avcpl]

since hydrocodone is often paired with APAP, make sure you're not also potentiating it too, since it is also metabolized through glucuronidation.

I'm wondering if anyone has tried Milk Thistle to potentiate hydromorphone? Dilaudid has notoriously short legs and since milk thistle inhibits UGT2B7, it might be the way to go.

I've heard of people using it successfully for oxycodone, but there are big variances in the quality of milk thistle (this link talks a little about it: http://www.salamresearch.com/html/milk_thistle_product.html )

 

[nj754]

And by doing so you would be stopping the morphine from then being converted to M6G.

I acknowledge that.

You aren't going to get anywhere with codeine other than inducing CYP2D6. Unless your 2B7 inhibitor had an extremely short half-life.

I agree that codeine doesn't look all that promising. But morphine itself is active, so it's hard to predict whether it would be a win without doing actual experiments.

I think time would be better spent figuring out how to increase hydrocodone -> hydromorphone, and oxyC -> oxyM. And preventing elimination through glucuronidation.

Selective 1A3 inhibition seems to be the most useful.

I think blocking glucuronidation is key to feeling any effects from that metabolic pathway. Since the HM and OM are being produced in the liver, I speculate that the amounts needed to be felt are more comparable to an oral dose than an IV one. (http://www.bluelight.ru/vb/threads/581361-Oxycodone-gt-oxymorphone-via-CYP2D6-why-it-doesn-t-matter) Ketoconazole apparently blocks UGTs as well as 3A4, which would make it appear ideal for enhancing OC, and maybe also HC. My personal experiments with OC + ketoconazole and itraconazole seemed to bear this out -- it felt stronger and lasted longer.

 

[nj754]

since hydrocodone is often paired with APAP, make sure you're not also potentiating it too, since it is also metabolized through glucuronidation.

It's important to consider these things. APAP doesn't become toxic until it's metabolized, though, so if you're blocking that pathway, you may be in the clear.

I'm wondering if anyone has tried Milk Thistle to potentiate hydromorphone? Dilaudid has notoriously short legs and since milk thistle inhibits UGT2B7, it might be the way to go.

I've heard of people using it successfully for oxycodone, but there are big variances in the quality of milk thistle (this link talks a little about it: http://www.salamresearch.com/html/milk_thistle_product.html )

Could be worth a shot.