Clonazepam, unbound fraction during the distribution phase

[Kdem]

Does anyone have that in a chart or something like that ?

I have been able to find the bloodplasma levels after dosing, see http://celerion.com/wordpress/wp-co...rsus-Tablets-in-Healthy-Adult-Volunteers1.pdf

But I have been wondering about the unbound fraction. It makes sense that it is higher during the distribution phase/'duration of action' since that part actually exerts an effect.
I haven't been able to find anything of the sort.

 

[harmreductioninc]

Should be pretty low

 

[clubcard]

86% - low for a benzo.

 

[Kdem]

That's an old post of mine !

That 86 % is the plasma protein binding.
What I was actually asking in the first post how high the unbound fraction would be in the initial phase after taking the drug.
Given that the amount would be plentiful in the first few hours after taking the drug I would expect that the unbound fraction would be relatively high, compared to 12 hours later. But maybe I got it all wrong. Anyway, I wrote that post months ago.

 

[clubcard]

Well, I've never read one of your posts knowingly - but sure, maybe I did see it... isn't the correct answer the point of the exercise?

 

[Kittycat5]

Define distribution phase as it generally only applies to IV administration. There is a rapid climb to peak, followed by a rapid decline from that peak (this is the distribution phase) followed by a slow elimination phase. Because of the speed of the distribution, there wont be much effect from increased fraction unbound.

 

[Kdem]

Kittycat5,

(see chart)

Valid point regarding the distribution phase.
But let's say, during the first part of the duration of action, would the unbound fraction not be higher than later ?

 

[Kittycat5]

I read the charts but not sure which one you mean. Drugs will reach an equilibrium where unbound fraction remains relatively constant with amount eliminated. Perhaps early on it may vary but measurements of levels in tissue is incredibly difficult to plasma measurements so you really just know what the unbound fraction is there with the various blood proteins and consider everything in tissue as being "used."

 

[clubcard]

I believe the very lowest protein-bound benzo is pyrazolam. The compound is excreted 100% unmetabolised. Hence short duration. STRONG affinity matched with lower cLogP BUT with a good pKa (at blood pH) for fast onset.

The scaffold is unique in that the -Br can be swapped for other halogens, pseudohalogens, alkynyl groups, nitro groups... and so on. The point is, just by changing 1 atom, you can get virtually anything from an alcohol pill through a Lude-like pill through to potent hypnotics and potent anxiolytics with minimal abuse potential. Not really an RC, but since it's public knowledge, nobody can patent it.