Posted by Larry Hoover on April 6, 2009, at 8:29:39
In reply to Re: How are reuptake ratios expressed?, posted by sowhysosad on April 5, 2009, at 22:24:12
> I think I've sussed it: the ratios relate to inhibitor affinities expressed in Ki nM.
>
> In Ki nM a LOWER number is BETTER, so the normal logic of a ratio is reversed, ie. the lower value in the ratio represents the higher affinity.You have to be careful about how you interpret Ki. The unit is nanoMolar, which is a concentration term. It's the concentration at which a substance occupies 50% of the available active sites. It's a dynamic measurement, as molecules are constantly binding to, and departing from, the active site. You're quite right; the lower the value, the higher the affinity.
In the case of transporters, binding to the active site can reasonably be interpreted as inhibition. Just as you can't park two cars in the same parking spot, if the transporter is occupied by an antidepressant, it can't transport its normal payload.
It's a little different when you start talking about receptors, because binding is only part of the picture. The receptor response to that binding is the other part. The substance binding there, the ligand, can activate the receptor (i.e. it is an agonist), it can partly activate it (partial agonist), it can just sit there and do nothing (competitive inhibitor), it can produce a negative response (reverse agonist), or other effects. These are all acute effects. Then you have to consider the downstream processes initiated by binding. Much more complicated than transporter binding effects.
You can look up Ki values in this database:
http://pdsp.med.unc.edu/pdsp.phpIn the opening page, what you want to do is put the chemical name of the drug (e.g. venlafaxine, not Effexor) into the test ligand box, and hit enter. You'll get a page with (hopefully) an array of data to consider.
Towards the left, you have the specific receptor identified. You'll need to know that serotonin is call 5-HT. I think all the others are straight forward. The Ki is in the middle column. But you'll also need to consider the "Hot ligand", the substance being displaced, and the species from which the receptor is drawn. The former criterion is very important when considering transporter binding, as the displaced substance should e.g. be serotonin when you're looking at serotonin transporter binding affinity, not some other drug. And the species matters, because we're not rats or whatever.
But even this information is just a starting point in assessing a drug. Individuals differ in their receptor density (regulation), receptor structure (genetics), parent drug to metabolite ratios (both regulatory and genetic), presence/absence of co-factors (receptor sensitivity modifiers of many types), and so on.
In the end, what matters is can you tolerate the drug, and does it help. Typical binding affinities help us to predict what will happen, but in the end, you have to do the experiment itself to know what happens in your body.
Lar
poster:Larry Hoover
thread:888069
URL: http://www.dr-bob.org/babble/20090330/msgs/888941.html