Combining the CYP3A4 inhibitor ketoconazole with oxycodone, hydrocodone etc.

[redeemer]

Combining the CYP3A4 inhibitor ketoconazole with methylated morphine derivatives

The enzyme CYP3A4 converts methylated morphine derivatives (oxycodone, hydrocodone, codeine) to a pharmacologically inactive substance. According to this study ketoconazole and troleandomycin inhibited the conversion of hydrocodone to the inactive norhydrocodone.

Would a combination of an appropriate dose of ketoconazole and hydrocodone, oxycodone or codeine be safe, ie. would the inhibition cause an overdose or just prolong the effects?
If so, what would the respective doses of the enzyme inhibitor and the opioid be?

 

[fastandbulbous]

Pick a one that isn't an antibiotic/antifungal agent otherwise you run the risk of getting a disease that's resistant to one of those agents because of incomplete & occasional exposure to said drugs preferring survival of drug resistant microorganisms.

How would you like athlete's foot to become athlete's foot, leg & crotch?

 

[redeemer]

^ OK. Would you deem this combination unsafe even if done very rarely, once every 2 months for example.

If so, do you know of any non-antibiotic/antifungal OTC CYP3A4 inhibitors and would the risk of an overdose from this combination be too great?

 

[fastandbulbous]

Just put 'cytochrome P450 inhibitors' into google and chances are you'll get a table of inhibitors of all the isoenzyme forms to take your pick from

 

[GABAlover]

Pick a one that isn't an antibiotic/antifungal agent otherwise you run the risk of getting a disease that's resistant to one of those agents because of incomplete & occasional exposure to said drugs preferring survival of drug resistant microorganisms.

How would you like athlete's foot to become athlete's foot, leg & crotch?

It's possible, I suppose. Far more serious possible consequences exist for the use of ketaconazole. If you really must try this experiment, I strongly advise you to find a safer 3A4 inhibitor.

 

[fastandbulbous]

^ Well indiscriminate prescribing and non-completion of courses given of antibiotics is how we now have nightmares like MRSA & strains of TB that don't respond to any antibiotic...

 

[almost-]

I hope you do know that ketoconazole is also a PGP-inhibitor and what that means.

http://www.bluelight.ru/vb/showthread.php?p=4111149#post4111149

Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4:
Finally, a 200-ml soup containing 1 g of black pepper (Velpandian et al., 2001) will contain about 1.1 mM piperine (Jensen-Jarolim et al., 1998) and local (intestinal) concentration might be in the range of our obtained IC50 and Ki values and will most likely result in inhibition of intestinal P-glycoprotein and CYP3A4.

Full text: http://jpet.aspetjournals.org/cgi/content/full/302/2/645

 

[GABAlover]

^ Well indiscriminate prescribing and non-completion of courses given of antibiotics is how we now have nightmares like MRSA & strains of TB that don't respond to any antibiotic...

That and the fact the general public often demand antibiotics, while refusing to do anything to improve their own health.

I agree that antibiotic resistance could be slowed, but it will always exist. Bacteria reproduce, and therefore evolve, so quickly that they will always be able to defeat a drug, given enough time.

Anyhow, aren't we talking about ketaconazole here? That's an azole antifungal agent.

 

[raybeez]

That and the fact the general public often demand antibiotics, while refusing to do anything to improve their own health.

I agree that antibiotic resistance could be slowed, but it will always exist. Bacteria reproduce, and therefore evolve, so quickly that they will always be able to defeat a drug, given enough time.

Anyhow, aren't we talking about ketaconazole here? That's an azole antifungal agent.

At least when the public inappropriately demands antibiotics, they take them all, start to finish. They don't just take one or two pills then toss the rest of the script. And antifungal drugs exert the same natural selection pressure on fungal pathogens as do antibiotics/bacteria -- in the end, they will select for resistant organisms.

 

[morphiquet]

@almost:

that document about piperine's quite interesting. it obviously suppresses cyp3a4-enzymes and could therefore also be used to inhibit n-demethylation of several opioids (e.g. tramadol, codein, ...) to greatly expand their half-lives.

but does anybody know which pgp-subtype is exactly responsible for effluxing loperamide out of the brain?

and how is loperamide metabolized?

i remember that some time ago, i read an article which claimed that loperamide's high first-pass metabolism contributes a lot to its lacking cns-activity (that means, that loperamide is only "topically" active in the bowel and as soon as it's uptaken into the blood, it's inactivated by the liver)
might the cyp3a4-enzyme be the one that implements this process?

buff, rarely write that much in english and appreciating your thoughts

 

[redeemer]

So, if I were to find an OTC inhibitor would it be safe enough to use in combination with the opioids mentioned above or is this too much of a generalization to make? Or, is this too much of a generalization to make and can this question only really be answered for a specific dose of a specific drug, perhaps for a speficic person since enzyme levels can vary greatly from person to person?

 

[SpunkySkunk347]

At least when the public inappropriately demands antibiotics, they take them all, start to finish. They don't just take one or two pills then toss the rest of the script. And antifungal drugs exert the same natural selection pressure on fungal pathogens as do antibiotics/bacteria -- in the end, they will select for resistant organisms.

This really scares me, because I was prescribed ketaconazole a year or two back for tinea versicolor.
The tinea versicolor is ALL OVER my chest, upper body, shoulders, and neck..
It wasn't going away after I tried my doctor's recommendation of using anti-dandruff shampoo as a lotion on affected regions right before taking a shower (doing this ended up giving me chemical burns), so a different doctor I went to ended up just handing me a script of ketaconazole with very little explanation as to how I was supposed to use it, how long I was supposed to use it, possible side effects or consequences from using it (drastically reduced testosterone levels, for example).
He did however tell me that I can't completely cover myself in ketaconazole lotion in ALL affected areas, and told me just to do small patches at a time.
I used it maybe 2-4 times, and didn't notice any results so I just never used it again.

I am scared that I will never get rid of this tinea versicolor -- thank god it isn't contagious... But has that doctor's negligence caused my fungal infection to evolve into some sort of super fungal infection?

Sometimes the symptoms of this infection are downright frightening; imagine not being able to sweat at all behind your ears or on the back of your neck, and it feels like you're being cooked so you have to constantly go to a bathroom and splash water on your face.

Also, does anyone know how long ketaconazole stays in your system? I'm assuming some of it inadvertently gets absorbed transdermally... If I ever end up using it again, how long should I wait before I can safely take methadone, oxycodone, or other opiates?