(If I made a mistake with the below, please let me know. I'm noticing this sort of miscalculation in all sorts of places.)
I was reading Stahl's paper on trazodone, and he theorizes a great deal based on trazodone's predicted receptor occupancy. For example, that 5-HT2a antagonism cannot solely explain trazodone's hypnotic effect, because it is 50% occupied with 1 mg but hypnotic dose is 25+ mg. That surprised me, so I did some digging.
Some background and other numbers:
- Kd of trazodone for 5HT2a receptor is ~35 nM
- 1 mg of trazodone PO achieves 37 nM serum Cmax, and dose:concentration is linear (i.e. 25 mg = 925 nM)
- Also, reported serum level for antidepressant effect is 1.75 uM
At Cmax, the occupancy of 5-HT2A by trazodone by itself is:
1 mg: ~50%
25 mg: ~96%
1.75 uM: ~98%
600 mg: ~99.8%
That all checks out until you factor in that trazodone is competing with serotonin, which has a Kd of ~1 nM for 5-HT2a and a CSF concentration of at least tens of nM, and an intrasynaptic concentration when released in the mM range.
When you factor in that it is competing with basal serotonin (let's say 50 nM to be conservative), the occupancy is instead:
1 mg: ~2%
25 mg: ~31%
1.75 uM: ~50%
600 mg: ~91%
When competing with serotonin released into the synapse the occupancy at all doses is negligible.
I was reading Stahl's paper on trazodone, and he theorizes a great deal based on trazodone's predicted receptor occupancy. For example, that 5-HT2a antagonism cannot solely explain trazodone's hypnotic effect, because it is 50% occupied with 1 mg but hypnotic dose is 25+ mg. That surprised me, so I did some digging.
Some background and other numbers:
- Kd of trazodone for 5HT2a receptor is ~35 nM
- 1 mg of trazodone PO achieves 37 nM serum Cmax, and dose:concentration is linear (i.e. 25 mg = 925 nM)
- Also, reported serum level for antidepressant effect is 1.75 uM
At Cmax, the occupancy of 5-HT2A by trazodone by itself is:
1 mg: ~50%
25 mg: ~96%
1.75 uM: ~98%
600 mg: ~99.8%
That all checks out until you factor in that trazodone is competing with serotonin, which has a Kd of ~1 nM for 5-HT2a and a CSF concentration of at least tens of nM, and an intrasynaptic concentration when released in the mM range.
When you factor in that it is competing with basal serotonin (let's say 50 nM to be conservative), the occupancy is instead:
1 mg: ~2%
25 mg: ~31%
1.75 uM: ~50%
600 mg: ~91%
When competing with serotonin released into the synapse the occupancy at all doses is negligible.
