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The pharmacokinetic CYP inhibition time window??

JohnBoy2000

Bluelighter
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May 11, 2016
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So drugs taken orally pass through the liver before being taken to the brain.

Correct me any time here, cause I'm just stringing together pieces of information.

The liver - from what I understand - is where by far the greatest concentration of CYP enzymes resides.

Thus - say there was a drug that was known to inhibition CYP2D6 - being taken in conjunction with another drug that is a sensitive subject of this enzyme.

Could drug interference be reduced or avoided by dosing with a time gap consistent with the Tmax of the drug dosed first?


So say one was taking Fluoxetine with - Desipramine; just by example.

Fluoxetine is a potent CYP2D6 inhibitor - desipramine's major metabolic pathway is CYP2D6.

Dosed together - the plasma levels of desipramine are going to soar.

But say desipramine is dosed 5 to 8 hours (the Tmax of fluoxetine) after fluoxetine - thus, presumably, most or all of the fluoxetine has passed through the liver - thus there would be less potential for the desipramine metabolism to be inhibited by the fluoxetine.

Does that make any sense?


Does it work like that - or no?
 
If fluoxetine irreversibly inactivates CYP2D6, then you would actually have the highest level of cyp2d6 inhibition 8 hours later(or at least higher than 1 hour after ingestion). Your body would need time to replenish its enzyme stores. Like when you are taking GFJ to increase levels of some benzo, or any drug, from what I know its more effective to take the GFJ 12 hours in advance, than 30 minutes in advance.

If fluoxetine only reversibly inhibits CYP2D6, then it could work something like that, but I don't know that details as far as timing are concerned. But I imagine it is an irreversible inhibitor. It's like the difference between reversible MAOI's and irreversible MAOI's.
 
The drugs in question are Lexapro, and Effexor.

I google searched "reversible cyp inhibition" for each - but nothing came up.

Any pointers as to how I'd find out whether either of those drugs are reversible or non-reversible cyp inhibitors?
 
A cursory search led to a few references to fluoxetine as a reversible competitive inhibitor of CYP2D6, but its inhibition seems fairly complex affecting multiple enzymes and creating different drug-drug interactions. I didn't spend a lot of time on it, but I didn't see anything that would answer your questions directly, in fact I think the only way to be sure something like that existed would be to find a study concerning those specific drugs and even then it will become less relevant over time(as in the longer you have been taking said drugs).

https://www.ncbi.nlm.nih.gov/pubmed/10631623
http://dmd.aspetjournals.org/content/dmd/31/3/289.full.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029899/
 
Thanks so much for posting them studies.

I have a little better insight into reversible/irreversible cyp inhibition now - but like you said, there's sparse specific information on the drugs I'm looking for.

What I did come across was, like you said, reversible or time-dependent inhibition is the case for fluoxetine, and duloxetine.

Paroxetine seems to exhibit potent and irreversible cyp2d6 inhibition - and I'm basically just continuing to trawl google scholar for a mention of venlafaxine and escitalopram, possibly sertraline - as to their cyp inhibition status.
 
https://journals.lww.com/psychophar...al_Time_Course_of_Cytochrome_P450_2D6.10.aspx

This study seems to delineate the time course of cyp2d6 inhibition, comparing fluoxetine, paroxetine and sertraline.

Fluoxetine exhibits the longest by far - then sertraline, then paroxetine.

The fact that paroxetine is an irreversible inhibitor - but has shorter inhibition time than sertraline - indicates, I don't know what.

I can't find anything on sertraline to determine whether it's irreversible or reversible - but I'm obviously inferring that, being more potent than paroxetine - that perhaps it is irreversible?
 

That initial chart seems to indicate that sertraline has greater inhibition potency that escitalopram which - strictly in terms of Cmax and AUC elevation - contradicts other more specific studies, stating escitalopram is a more potent inhibitor.

However - what those other studies don't take into consideration is, the time dependence of escitalopram or sertraline inhibition - so I'm left to assume their ultimate deduction factors that in - so perhaps sertraline is an irreversible inhibitor?

Surely there's gotta be a more specific way to find that information?
 
You'd imagine that CYP inhibition is dependent on the dose strength taken - which seems to be the case for sertraline - but not fluoxetine and venlafaxine.

Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine

Via:

https://www.ncbi.nlm.nih.gov/pubmed/10631623


So theoretically - one could go much higher dose venlafaxine or fluoxetine, without exacerbating inhibition.

How that works.....
:?
 
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