Posted by tensor on January 22, 2007, at 5:35:33
In reply to Zoloft and dopamine reuptake inhibition, posted by Quintal on January 19, 2007, at 21:12:03
I think the difference between Zoloft's and Wellbutrin's dopamine action is pretty good explained by SHELDON H. PRESKORN, MD.:
Tables 1 and 2 provide the data needed to understand why bupropion affects the dopamine and norepinephrine uptake pumps while sertraline does not. The differences between the plasma levels of sertraline and those of bupropion plus its metabolites occur because of rather than in spite of the substantial difference in the binding affinity of bupropion and sertraline for their respective targets. The levels of sertraline are so low because of its high binding affinity for the serotonin uptake pump. In contrast, the level of hydroxybupropion alone is 100 times higher than the level of sertraline because such high concentrations are needed to block the dopamine and norepinephrine uptake pumps, given the low affinity of bupropion for these targets.
Table 1. Mean (and standard deviation) trough plasma levels (ng/ml) of bupropion and its three major metabolites in patients on 450 mg/day of immediate release forumulation.*
Bupropion 33 (34)
Hydroxybupropion 1452 (666)
Erythrohydrobupropion 138 (86)
Threohydrobupropion 671 (425)Table 2. Relationship between sertraline dose, mean trough plasma level and magnitude of serotonin uptake inhibition in platelets.*
Dose 50 mg
Mean drug level 16 ng/ml
SE uptake inhibition of platelets 80%Based on the comparison of binding affinities shown in Figure 1, the levels of sertraline needed to block the dopamine uptake pump are clearly lower than the levels of bupropion needed to block this pump. However, the serotonin uptake pump would be saturated at such concentrations of sertraline. In an earlier column,19 the dose-(and hence concentration-) dependent nature of sertraline's inhibition of the serotonin uptake pump was presented. Based on those results, a dose of 200 mg/day in the average patient produces sertraline concentrations that yield over 95% inhibition of the serotonin uptake pump. Given the difference in sertraline's binding affinity for the serotonin versus the dopamine uptake pump, the dose of sertraline needed to block the dopamine uptake pump would be substantially higher than 200 mg/day. Nevertheless, this statement is tentative since there have been no formal, human studies done to determine what dose of sertraline would be needed to achieve concentrations of sertraline sufficient to block dopamine uptake nor how many people could tolerate such a dose in terms of the serotonin adverse effects likely to result from such a saturation of the serotonin uptake pump.
The bottom line is that the 20-fold difference between sertraline and bupropion in binding affinity for the dopamine uptake pump (Figure 1) is more than offset by the 100-fold difference in the drug concentrations of each achieved under their usual dosing conditions (Tables 1 and 2). Parenthetically, notice that the difference in concentration between these two drugs is several times higher than the difference in their dose (50 to 450 mg/day, respectively). Remember that dose is only one of the two factors that determine drug concentration (Equation 2). That is the reason why dose is an imperfect way of assessing the potency of a drug in terms of an action.
-------The whole article can be read at http://www.preskorn.com/columns/0001.html
/Mattias
poster:tensor
thread:724214
URL: http://www.dr-bob.org/babble/20070119/msgs/725080.html