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Enzymes (eg CYP2D6/CYP3A4) and Inhibitors/Inducers

mcwally

Bluelighter
Joined
Jan 16, 2008
Messages
717
Heyas, I have a few questions regarding these enzymes and some of the terminology. Most of my queries/info is from wiki to keep it reasonably simple and less time consuming

CYP2D6 - a substrate for things like codeine, tramadol, venlafaxine (effexor - SNRI), DXM
Ok so a substrate of an enzyme means it is partially or wholey responsible for metabolising these substances and hence making them 'work'? If one was on say venlafaxine (and had a normal genotype regarding this enzyme) does this mean that doses of say codeine or DXM would be much less effective because CYP2D6 is also busy metabolising the efexor? (particularly if it is time release XR)

In addition it seems that much SSRIs are both substrates and inhibitors of CYP2D6 (and from reading on here codeine is also). Inhibitor - binds to the CYP2D6 enzyme and decreases it's effectiveness? But codeine is not in the inhibitor list of CYP2D6 or CYP3A4 enzymes, and I have read on here that redosing it doesnt work because it is itself an inhibitor of its metaboliser. wtf?

So to make a drug more effective we want an inducer of the relevant enzyme right? Or do we want an inhibitor to make the drugs effect last longer. I need some clarity on these points pls :) eg grapefruit juice is an inhibitor of CYP3A4 but is reccomended as a potentiator for say codeine, which is metabolised by both CYP3A4 & CYP2D6.......

CYP3A4 seems to be a substrate of heaps of gear like benzos, antipsychotics, SSRIs, DXM, codeine, fentanyl, barbituates, zopiclone etc. So arent we looking for inducers of CYP3A4 to increase the metabolic rates for these drugs? But from reading on here the grapefruit juice and cimetidine which are inhibitors of CYP3A4 potentiate codeine/opiates??

Lastly the enzyme that metabolises zolpidem (ambien/stilnox) is apparently CYP34A, now is that definately a different enzyme than CYP3A4!! :! Anyone know any inducers/inhibitors of CYP34A?

Thanx for reading this just need some enzyme action/terminology straightening for interests sake and to keep my medications working and also the recreactional ones ;)

cheers, mcwally
 
CYP2D6 is the enzyme responsible for demethylating codeine morphine, so you want to induce (increase) it's activity.

CYP3A4 is the enzyme responsible for metabolizing morphine to inactive products, so we want to inhibit (decrease) it's activity.

Despite grapefruit juice inducing CYP3A4 (which we don't want), it still has appreciable enough activity in inducing CYP2D6 that it's worthwhile - so what ends up happening is you get a more intense (because of greater demethylation to morphine proportion) but shorter-lived high (because CYP3A4 is destroying the produced morphine faster than usual).

Different drugs use different enzyme systems. Sometimes enzymes will make changes to a molecule that make it more potent - for example, tramadol is converted to O-desmethyltramadol, which is many times more potent. Other times (and much more commonly), an enzyme will make changes to a drug that renders it inactive, and it is passed out of the body.
In order to predict the effects of induction and inhibition on different enzymes and how they will affect the drugs you are taking, you must first know the effects of the different enzymes on the drug you're looking at.
 
You only want to induce enzymes if the drug you are taking is metabolised into a more active form, i.e. codeine, dihydrocodeine, hydrocodone, tramadol, and possibly oxycodone and buprenorphine. With codeine, dihydrocodeine and hydrocodone, the parent drug has very little activity, and so you want to induce CYP2D6 as much as possible, which strips off the 3-methyl group to make the active 3-hydroxy form.

With tramadol and oxycodone both the starting compound and the metabolite are active, so inducing the enzymes could be bad or good depending on your individual physiology, if you induce CYP2D6 enough then this may increase their effects, but as Mattpsy points out if you induce CYP3A4 then this will shorten the duration, so really you want to induce CYP2D6 and inhibit CYP3A4.

(and yes the action of oxycodone is affected by the oxymorphone metabolite even though its only produced in small quantities, see "Lemberg KK, Kontinen VK, Siiskonen AO, Viljakka KM, Yli-Kauhaluoma JT, Korpi ER, Kalso EA. Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats. Anesthesiology. 2006 Oct;105(4):801-12.")

With buprenorphine the N-demethylated metabolite is actually more active than the parent compound, so CYP3A4 is the enzyme you want to induce.

With most other medicines, the compound you take is the active form already, and inducing enzymes will just metabolise it faster and make it not last so long.
 
I'm pretty sure that chronic smoking/drinking does induce one of those enzymes. No time too look now, would appreciate feedback.

Just a note.
 
kk im getting the picture cool thnx, still some points though,

MattPsy said:
CYP2D6 is the enzyme responsible for demethylating codeine morphine, so you want to induce (increase) it's activity.

CYP3A4 is the enzyme responsible for metabolizing morphine to inactive products, so we want to inhibit (decrease) it's activity.

Despite grapefruit juice inducing CYP3A4 (which we don't want), it still has appreciable enough activity in inducing CYP2D6 that it's worthwhile

according to wiki (I know its not the be all and end all tho) the grapefruit juice isnt listed as an inducer of CYP2D6, but is listed as an inhibitor of CYP3A4.......Can we clear that one up still a bit confusing

and say with zolpidem it is the active compound already right? so looking into inducers/inhibitors for it for example is a waste of time?
 
Yeah, zolpidem is definitely the active compound. Considering that it kicks in within 10-20 minutes of swallowing a tablet, it really has to be.

Looking for an enzyme inhibitor isn't a bad idea, though, if you're looking to extend the effect.
 
^kk tar

but the enzyme that metabolises zolpidem (ambien/stilnox) is apparently CYP34A, now is that definately a different enzyme than CYP3A4?
 
mcwally said:
according to wiki (I know its not the be all and end all tho) the grapefruit juice isnt listed as an inducer of CYP2D6, but is listed as an inhibitor of CYP3A4.......Can we clear that one up still a bit confusing

The flavanoid in grapefruit juice is an inhibitor of CYP3A4, not an inducer (you want an inhibitor to slow the N-demethylation of opiates eh morphine --> normorphine). Also, to my knowledge it has bog all effect on CYP2D6

Clearer now? :)
 
so if we inhibit CYP3A4 its basically what we want for slowing the breaking down of morphine, zolpidem/zopiclone and even most benzos!! not giving a stronger high necessarily but a longer one

done some more reading on wiki, looks like we want bergamottin (in grapefruit juice) and quercetin which is the flavonoid, in citrus fruits, apples, berries, red wine.

hmmm might look for some supplement/vitamin tablets with these in em me thinks ;)
 
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mcwally said:
Lastly the enzyme that metabolises zolpidem (ambien/stilnox) is apparently CYP34A, now is that definately a different enzyme than CYP3A4!! :! Anyone know any inducers/inhibitors of CYP34A?

I don't understand this sentence: CYP3A4 is not CYP3A4??
 
^CYP3A4 is the more commonly known enzyme here

CYP34A is what wiki says metabilises zolpidem but Im unsure if it is a typo or actually a different enzyme still really
 
Oh sorry...my fault...i didn't see the A-4 vs. 4-A difference. Really tricky.:\ It's a "typo" as you called it. Reason: The nomenclature system goes like this:

CYP = superfamily
3 = family (similarity in the amino acid sequence >40% )
A = subfamily (similarity >55% )
4 = number of the isoenzyme

And all CYPs are named like this. Therefor it makes no sense to name a CYP "CYP34A".

Peace! Murphy
 
Dammit! There was even more but I was logged out from BL...so again..:(

Here is a list of CYP3A4-modulators as well as substrates. The list is taken from http://www.uspharmacist.com/oldform.../druginteractions.cfm&pub_id=8&article_id=704, and there you can also find a similar listing for CYP2D6-interactions.

Highlighted substances in red are considered as of higher interest for Bluelighteners (my own selection).

3A4 inhibitors: Cimetidine, Clarithromycin, Clotrimazole, Delavirdine, Diltiazem, Erythromycin, Fluconazole, Fluoxetine, Fluvoxamine, Grapefruit juice (6,7-dihydroxybergamottin), Indinavir, Intraconazole, Ketoconazole, Metronidazole, Mibefradil, Miconazole , Nefazodone, Nelfinavir, Nifedipine, Norfloxacin, Omeprazole, Paroxetine, Propoxyphene, Quinine, Ritonavir, Saquinavir, Sertraline, Troleandomycin, Verapamil, Zafirlukast

3A4 substrates: Alfentanil, Alprazolam, Amiodarone, Amlodipine, Astemizole, Benzphetamine, Carbamazepine, Cilostazol, Cisapride, Chlorpromazine, Clarithromycin, Clonazepam, Cocaine, Cortisol, Cyclophosphamide, Cyclosporine, Dantrolene, Dapsone, Delavirdine, Dextromethorphan, Diazepam, Digitoxin, Diltiazem, Disopyramide, Enalapril, Erythromycin, Estradiol, Estrogen, Ethosuximide, Ethylmorphine, Etoposide, Felodipine, Flutamide, Fluconazole, Indinavir, Itraconazole, Ketoconazole, Lidocaine, Loratadine, Lovastatin, Mephenytoin, Miconazole, Midazolam, Nefazodone, Melfinavir, Nevirapine, Nicardipine, Nifedipine, Omeprazole, Paclitaxel, Paracetamol, Prednisone, Propafenone, Progosterone, Quetiapine, Quindine, Ritonavir, Saquinavir, Sertraline, Simvastatin, Tacrolimus, Tamoxifen, Testosterone, Triazolam, Venlafaxine, Verapamil, Vinblastine, Warfarin (R isomer), Zolpidem

3A4 inducers: Carbamazepine, Dexamethasone, Ethosuximide, Isoniazid, Nevirapine, Phenobarbital, Phenytoin, Prednisone, Prednisone, Rifabutin/Rifampicin

Notice that some substances are substrates AND modulators at the same time... Also, co-administration is not uncommon (as suggested by some guys in this thread), even it is normally not for enhancing psychoactivities. A well known example: HIV-patients get some of their medication together with Ritonavir because the first-pass-effect of the remedies is far too high. Ritonavir, which actually is a virostaticum, doesn't affect the HI-virus in the very most cases and is only administered as modulator. Due to the heavy sideeffects of Ritonavir I would strongly disencourage such a modulation for psycho-enhancement. But the above lists offers more then just 1 possibility to play around with your liver.

Peace! Murphy
 
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You only want to induce enzymes if the drug you are taking is metabolised into a more active form, i.e. codeine, dihydrocodeine, hydrocodone, tramadol, and possibly oxycodone and buprenorphine. With codeine, dihydrocodeine and hydrocodone, the parent drug has very little activity, and so you want to induce CYP2D6 as much as possible, which strips off the 3-methyl group to make the active 3-hydroxy form.

I thought dihydrocodeine was already an active substance, that the amount of hydromorphone that it is metabolized into is insignificant.
 
...Chronic smoking? Why is it so hard to find its effects on liver enzymes!
 
Just thought I'd add one to the substrate lists that might be of interest:
Ketamine (metabolism to norketamine)

For people wanting to get the most out of their codeine derivative drug, you want a CYP3A4 inhibitor and a CYP2D6 inducer, pref in a single compound if possible, to speed up O-demethylation & slow down N-demethylation so you end up with higher plasma concentrations of the morphine derivative
 
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So I getting that grapefruit juice and Cimetidine would work well together?

I usually do GFJ and 75mg Benedryl but never added in Cimetidine with my hydrocodone.
 
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