Interaction potential of Escitalopram/Lexapro??

[JohnBoy2000]

SSRI's supposedly all interact with CYP2D6, which is responsible for metabolism of many psychoactive drugs - thioridazine, several AP's, etc.

Lexapro seemingly has the lowest interaction potential of any SSRI.

Anyone have experience with the degree to which it may actually interact with other drugs?

Have you found dose adjustment of the combination agent being necessary?

Doesn't seem to be too much information as to interaction potential on it - but it is noted that it mildly inhibits CYP2D6 in literature.

Also - what is referred to as "clinically significant" in literature, I believe refers to implication of plasma levels to below 30%, which, in my opinion, is actually significant enough.

Leaving this here - for later review; from FDA pages on Lexapro and Effexor:


Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in thepresence of venlafaxine. The 2-OH-desipramine AUC?s increased by at least 2.5 fold (withvenlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did notaffect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated2-OH-desipramine levels is unknown.


*****
Drugs Metabolized by Cytochrome P4502D6 - In vitro studies did not reveal an inhibitory effect of escitalopramon CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggestingthat coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significanteffects on escitalopram metabolism.

However, there are limited in vivo data suggesting a modest CYP2D6inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclicantidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax anda 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless,caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.

Metoprolol - Administration of 20 mg/day LEXAPRO for 21 days in healthy volunteers resulted in a 50%increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministrationof LEXAPRO and metoprolol had no clinically significant effects on blood pressure or heart rate.

**
In a controlled study of healthy male volunteers, multiple doses
of citalopram 40 mg significantly increased single- dose desipramine plasma levels (50% rise
in desipramine AUC).

 

[oxyloveUK]

Tramadol very bad idea to combine of course

 

[JohnBoy2000]

In relation to CYP2D6 inhibition on Atomoxetine - via FDA website:

In Extensive Metaboliser individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone.

Is that basically the equivalent of, what - taking 3 to 4 times the dose you're actually taking??



Edit:

Taken from: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2125.1996.tb00173.x

2 Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6‐dependent dextromethorphan O‐demethylation were: 33, 52 and 22 μM for rac‐venlafaxine, R(+)‐venlafaxine and S(‐)‐venlafaxine, respectively, vs 0.065 to 1.8 μM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline.


Would suggest - venlafaxine has far less interaction potential than any of the other SSRI's.

Escitalopram isn't included there but, it's CYP2D6 inhibition is higher than sertraline - according to other papers.

 

[Hodor]

In relation to CYP2D6 inhibition on Atomoxetine - via FDA website:

In Extensive Metaboliser individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone.

Is that basically the equivalent of, what - taking 3 to 4 times the dose you're actually taking??

AUC = Area Under the Curve.
css, max = Maximum concentration at steady state

It is hard to translate this into a specific dose increase due to the non-linear nature of these enzyme kinetics, as well as the changes in the relative concentration of various potentially active metabolites (4-HO-atomoxetine, noratomoxetine); but yes, it is safe to say that this corresponds to a greatly increased dosage level.

That said, I do not think that taking a standard dose of 10 mg of Lexapro is going to present much of an issue in most cases. Before the availability of generic escitalopram and the updated prescription guidelines reflecting the potential for cardiac arrythmia, it wasn't all that uncommon for people to be on 80 mg of racemic citalopram (one would expect both isomers to have similar effects on cyp2d6). In a non-emergency medical setting, people are generally going to start low and titrate upwards anyway.

 

[JohnBoy2000]

What surprised me was - with Reboxetine - it's profile is basically, theoretical but non-clinically significant inhibition of CYP2D6, and moderate permeability glycoprotein inhibition.

However - in my case, it interacted heavily with Mianserin (which is only moderately metabolized by CYP2D6), to the point I had to cut it's dose in half to avoid night time activation.

So, where'd that interaction come from?

There is mention in one paper, something to the effect of an additional binding to alpha 1 acid-glycoprotein, which may affect combination agents which are heavily protein bound.

Mianserin - is 95% protein bound, with a corresponding bioavailability.

I don't know to what degree SSRI's or SNRI's like effexor would implicate alpha 1 acid-glyoprotein and affect metabolism of highly protein bound drugs - but, Atomoxetine is 99% protein bound so - if it does, it might - how you say - fuck my shit up, in several undesirable ways.

Perhaps someone here is more familiar with them agents in that capacity?

 

[Hodor]

Doesn't Mianserin have some weird-ass pharmacology that is based on alpha-2 autoreceptor antagonism to enhance noradrenergic neurotransmission? (in addition to having atleast some NET inhibition, unlike mirtazapine).

Maybe it's just tetracyclic antidepressants and NARI's being highly synergistic based simply on their mechanism of action, rather than CYP inhibition?

 

[JohnBoy2000]

Doesn't Mianserin have some weird-ass pharmacology that is based on alpha-2 autoreceptor antagonism to enhance noradrenergic neurotransmission? (in addition to having atleast some NET inhibition, unlike mirtazapine).

Maybe it's just tetracyclic antidepressants and NARI's being highly synergistic based simply on their mechanism of action, rather than CYP inhibition?

In regards to its pharmacology - yes - very similar to mirtazapine, but no 5HT effects.

There is a synergy, but I replaced reboxetine with atomoxetine, and previous to that was on lofepramine/desipramine in combination - with no undesirable outcome.

That's what baffles me:

There's no notably listed interactive potential with reboxetine - in fact, it seems to be marketable as highly combinable - but there was an unquestionable interaction.

I think cause it's so rarely used and therefore examined, there's basically not a lot of information on it.


For now all I can do is attribute it to alpha 1 acid glycoprotein - and do more google searches as to whether that's affected by the SSRI's and/or Effexor.

There are however many case studies of atomoxetine used to combat residual fatigue in SSRI treated patients with incomplete outcome - so, at least that alludes to the combination being feasible enough.


Convincing a Dr to script 3 drugs at one time - may be another kettle of fish.

 

[JohnBoy2000]

The interactive potential of venlafaxine with desipramine (which seems to be the benchmark for CYP2D6 metabolic inhibition), was a 30% AUC increase.

In terms of how that would translate..... I guess it's hard to answer?


Edit:

I'll be damned.

https://www.ncbi.nlm.nih.gov/pubmed/3931147

Mianserin - degree of protein binding was positively correlated to the concentration of alpha 1-acid-glycoprotein and complement C3c, and somewhat more weakly to haptoglobin

So perhaps in terms of that Mianserin - Reboxetine interaction, it actually was related to alpha 1 acid glycoprotein;
the mechanism, dispacement etc - yeah, pharmacokinetics, I'm lost.
That that would appear to be the correlation.


Edit 2:

That seems to be a primary consideration in regards to drug interactions - that I personally certainly never considered previously.

Percentage protein binding of each drug - the potential for one to displace the other.

As sertraline dose with warfarin by example.

 

[JohnBoy2000]

Okay -here's a question that may put your pharmacological minds to the test:


Atomoxetine - is 97.5 out of 98.5% bound to plasma protein albumin.

Venlafaxine - is 30% plasma protein bound - also to albumin.

Mianserin is bound primarily to alpha 1 acid glycoprotein - at 95% - so that's irrelevant.


The question: Could venlafaxine's 30% - potentially displace atomoxetine 95% - or vice versa??

I mean, I just don't know anything about plasma protein concentrations etc - perhaps one of ya'll more familiar with pharmacokinetics will have an insight here?

 

[CFC]

Yes, absolutely. However, what you need to understand is that just because 90%+ of a drug is bound to albumin, that doesn't mean all albumin is 90%+ occupied by that drug. There may be more than enough unbound albumin to blunt the effect of the second drug displacing a fraction of the first.

 

[JohnBoy2000]

Yes, absolutely. However, what you need to understand is that just because 90%+ of a drug is bound to albumin, that doesn't mean all albumin is 90%+ occupied by that drug. There may be more than enough unbound albumin to blunt the effect of the second drug displacing a fraction of the first.

That's what occurred to me but - then the first part of your reply.

Theoretically - there should be enough plasma albumin to accommodate both drugs plasma binding - but there's still the possibility of displacement?

 

[JohnBoy2000]

I got scripted Effexor at 75 mg.

Little bit of a tension headache and light headedness given the trio combination.
Today was 2nd day dosing it.

In one way - unquestionably feel better - but in another way, slightly phased out of it.

Think it will require dose adjustments of Strattera.

Can 37.5 mg venlafaxine given the combination - yield appreciable effects?

My concern is the common post synaptic phosphorylation pathway to SER and NA - maybe the boost being excessive.

 

[CFC]

That's what occurred to me but - then the first part of your reply.

Theoretically - there should be enough plasma albumin to accommodate both drugs plasma binding - but there's still the possibility of displacement?

Some will, though whether it really has relevant effects or not would require specific research, which afaik there hasn't been.

From what I remember, most research was really only on warfarin interactions, but there may have been more done in the decade or two (cough) since I last studied it

 

[JohnBoy2000]

I had a look through the warfarin based interactions with Lexapro.

They didn't seem to hold what is deemed, "clinical relevance".

However - given the therapeutic indices of atomoxetine and mianserin are so narrow - I would still be cautious.

Lexapro would be my favoured choice over Effexor - I know both work wonders on mood for me personally.

They say effexor has negligible effects on noradrenaline up to doses of 150 mg.

I'm curious as to how - outside of clinical observation of it not being particularly activating before that dose - they came to that conclusion?
From a pharmacological point of view, I mean?


Is it not possible in any capacity to contact say - an industry based pharmacologist or medicinal chemist - to acquire more precise insights into these areas?

 

[Cotcha Yankinov]

I'm curious as to how - outside of clinical observation of it not being particularly activating before that dose - they came to that conclusion?
From a pharmacological point of view, I mean?

They could either look at radioligand binding studies (NET PET occupancy), measure NE cell firing directly (especially in vitro with patch clamp techniques), or measure the concentration of NE with microdialysis. They can also look at metabolites of neurotransmitters, however that is rather indirect and there are control issues with that. For example, compensatory upregulation of monoamine oxidase

CY

 

[d1nach]

You could use Ic50 (nM) values for the NET

 

[JohnBoy2000]

https://www.sciencedirect.com/science/article/pii/S1359644611004545

From this paper - it's made clear that, Human serum albumin (HSA), is by far the most concentrated blood plasma protein - coming in at 35 - 50 mg/ml.

Alpha 1 acid glycoprotein - the other primary plasma protein, comes in at 0.5 - 1.0 mg/ml.

The other plasma proteins seem to be made up of lipoproteins of various incarnations.

**
As to sertraline - via FDA info:

Protein Binding–In vitro protein binding studies performed with radiolabeled 3H-sertraline
showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL.
However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and
N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol

...where at a max daily dose of 200 mg/day - typically equates to 200 ng/ml

Which to me translates as - despite being highly HSA bound - it pretty much won't interfere with other drugs via HPA displacement - largely due to the fact that, there's plenty of HPA to go around.

 

[JohnBoy2000]

Can anyone shed light on:

100% AUC increase.

Does that basically translate as, effectively taking double the drug dose of normal?

 

[CFC]

Which to me translates as - despite being highly HSA bound - it pretty much won't interfere with other drugs via HPA displacement - largely due to the fact that, there's plenty of HPA to go around.

Yes, which is why they generally don't tend to bother studying this kind of interaction. There's a lot of albumin.

Can anyone shed light on:

100% AUC increase.

Does that basically translate as, effectively taking double the drug dose of normal?

It means twice the bioavailability in whichever system it was measured from (eg blood serum), though not necessarily a doubling of the effect (pharmacodynamics).

 

[JohnBoy2000]

It means twice the bioavailability in whichever system it was measured from (eg blood serum), though not necessarily a doubling of the effect (pharmacodynamics).

Okay - that's the part I'm having difficulty understanding.

With drugs that have narrow therapeutic index - twice the bioavailability; first off, twice bioavailability - without the inhibitor combination drug causing the AUC increase, would that be the equivalent of taking twice the dose of the drug in question?

In other words - twice the bioavailability/exposure - but without twice the effects; how is that?​