4 replies to this topic

[kurdishfella]

The occupancy of dopamine transporter (DAT) sites by bupropion and its metabolites in the human brain as measured by positron emission tomography was 26% according to GlaxoSmithKline researchers .

 

in any case, the above findings suggest that, although weak DAT occupation may occur, oral bupropion at clinically-used doses does not have the actual capacity to elevate dopamine levels in the human brain.[14] In accordance with this finding, based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a significant mechanism of the drug's action. Moreover, 65%75% DAT occupancy is necessary for euphoria and abuse potential.[82]

Ki values of sertraline at the human SERT, DAT, and NET of 0.29, 25, and 420 nM, respectively.[93] The selectivity of sertraline for the SERT over the DAT was 86-fold.[93] In any case, of the wide assortment of antidepressants assessed in the study, sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrinedopamine reuptake inhibitors (NDRIs) nomifensine (Ki = 56 nM) and BUPROPION (Ki = 520 nM).[93][104] Sertraline also has similar affinity for the DAT as the NDRI methylphenidate (Ki = 24 nM).[93][104] Tametraline (CP-24,441), a very close analogue of sertraline and the compound from which sertraline was originally derived, is an NDRI that was never marketed.[109]

 

So if wellbutrin alone is 27% on DAT and sertraline has higher affinity for dat than wellbutrin it should equal more than 50% if taken together thus block DAT efficiently and increase dopamine neurotransmission right and produce anti depressant effect?  The text say sertraline has similar affinity for the DAT as the NDRI methylphenidate (ritalin).. I dont know how much that is .But the good thing with sertraline is its long half life 26 hours and ritalin has very short 7 hours or something similar.

Edited by farshad, 06 February 2018 - 06:02 PM.

[Nietzsche]

It is unclear to me what argument you're making, or what your goal is with inhibiting DAT to within a specific range. Both of those drugs do more than just inhibit dopamine reuptake. And you're oversimplifying the pharmacology... just a tad. I'm champing at the bit for more info....

[kurdishfella]

blocks DAT to increase dopamine together they block  over 50% dopamine transporter enough to produce an anti depressant effect 

im asking if i am correct if this makes sense?

Edited by farshad, 07 February 2018 - 03:29 AM.

[Nietzsche]

I understand what you're asking but I disagree with the premise that DAT inhibition alone is sufficient in and of itself for antidepressant action, or should be the ultimate goal when choosing a treatment.

 

It isn't that simple. We know that bupropion and sertraline both provide antidepressant effects, independently and they can certainly be synergistic in some patients (all SSRIs can be synergistic with bupropion, not just sertaline). True, both inhibit DAT, sertraline more so than the other SSRIs, but they have other mechanisms that contribute to this effect. So it isn't reducible just to inhibiting the dopamine transporter.

 

If you feel you need a high level of DAT inhibition, then yes, you'll likely get synergy from bupropion and sertraline, though it wouldn't simply be a purely additive effect as you're describing, nor should reaching a "threshold" of DAT inhibition be a goal of depression treatment.

 

Now, there's nothing wrong with that combo of meds.....but of course ask your MD, not some guy online who thinks he's Nietzsche.

Edited by Nietzsche, 07 February 2018 - 04:04 AM.

[kurdishfella]

oh nevermind wont work

from wiki

 

However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%.^[83] Hence, only 1.5% is free and theoretically bioactive.^[83] Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the K_i value that Tatsumi et al. found with sertraline at the DAT.^[93] A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM).^[83] This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the K_i of sertraline for the DAT.^[93]

As such, it seems unlikely that sertraline would produce much inhibition of dopamine reuptake even at clinically used dosages well in excess of the recommended maximum clinical dosage.