Methadone Metabolism

[jasoncrest]

I read many many webpages on Methadone metabolism, and learned that:
Methadone is metabolized to inactive products by:
-CYP2B6 mainly
-CYP3A4 plays also an important role
-CYP2D6
-CYP1A2
-CYP2C19 some sites say it's the most important enzyme in Methadone metabolism with CYP2B6, some other say in fact, it doesn't play such a big role...
-(CYP2C9 I'm not sure)

#1 First question:
is that ^ right? Is Methadone metabolized by another enzyme that I didn't mentioned?

I then looked for enzymes inhibitors. Because, if the enzymes are inhibited, Methadone won't be converted to inactive metabolites, the levels will be higher, the elimination slower...

Fluvoxamine (I'll get a script for it soon) inhibits 1A2, 2C19, 3A4
Cimetidine (I have a box of it) inhibits 1A2, 2C19, 2D6, 3A4
Chlorpheniramine (I have a box of it) inhibits 2D6.

So if I take high doses of these 3 substances, every enzyme that metabolize Methadone will be inhibited by 2 substances....
Except CYP2B6...

#2 Second question: do you know any CYP2B6 inhibitor?

#3 Third question: If I take high doses of my inhibitors, Methadone will be metabolized only by CYP2B6, right?
Will I feel a really stronger and longer-lasting effect?

#4 Is it dangerous to inhibits all these enzymes and take Methadone?

#5 Any other thing I should know?
Any advice for potentiation?

Thanks!

 

[jasoncrest]

I'm sad to see that no-one answered my questions...

Anyway, I have another, and don't want to open a new thread:

How Methadone Metabolism is affected by food?

Does eating before or after your dose alter the high (the time it takes to peak, its intensity)?

 

[BilZ0r]

Yeah, I tried to look into it, but I couldn't find the answers...

On the food subject, I did a little review on that somewhere a couple months ago, food increased the bioavailability of the most of the opioids I looked at, but decreased the Cmax and Tmax... i.e. the peak was less and look longer to come one, but you absorbed the drug more completely.

 

[jasoncrest]

Yeah, I tried to look into it, but I couldn't find the answers...

On the food subject, I did a little review on that somewhere a couple months ago, food increased the bioavailability of the most of the opioids I looked at, but decreased the Cmax and Tmax... i.e. the peak was less and look longer to come one, but you absorbed the drug more completely.

Thank you a lot.
But I don't understand something: if the drug is absorbed more completely, it should give a stronger effect? But you say the Cmax is decreased?

 

[BilZ0r]

No, because it takes a longer time for the peak to happen... if you were taking the drug for pain, this would be good, but for a high, bad.

The red line being with food.

 

[fastandbulbous]

Apparently if it's metabolized such that both methyl groups are removed from the nitrogen, it forms a heterocyclic compound by the formation of an imine (removal of a water molecule) which can rearrange internally; the article said something about different receptor affinities of this cyclic compound, but that's where my memory fails

 

[EN21]

I remember any interaction of grapefruit with CYP's , but I don't know exactly.

 

[jasoncrest]

I remember any interaction of grapefruit with CYP's , but I don't know exactly.

Grapefruit juice inhibits CYP3A4, which is the main enzyme that metabolizes Methadone to inactive metabolites.... So Grapefruit juice potentiate Methadone (eventhough there's CYP2B6, CYP2D6, CYP1A4, CYP2C19 and maybe some others that also metabolize Methadone to inactive products...)

 

[Eduard]

Methadone and grapefruit juice:

Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment.

Also

http://www.mayoclinicproceedings.com/inside.asp?AID=1616&UID=8934

methadone, and many of the HMG-CoA reductase inhibitors and dihydropyridine calcium antagonists have severe dose-dependent adverse effects. Grapefruit juice is known or presumed to cause a marked increase in the serum levels of these medications. The effect of grapefruit juice varies from patient to patient, at least in part because of wide variations in intestinal concentrations of CYP3A4. The effect is similar in magnitude to that with itraconazole and erythromycin, and so if a drug should not be taken with these medications, then it should not be taken with grapefruit juice either.