INHIBITORY EFFECT OF CLOMIPRAMINE AND RELATED DRUGS ON SEROTONIN UPTAKE IN PLATELETS - MORE COMPLICATED THAN PREVIOUSLY THOUGHT

Clomipramine and related tricyclic antidepressants are strong inhibitors of serotonin uptake in platelets and brain tissue. Usually, the inhibition in platelets has been reported to be competitive, but in some recent reports it is claimed to be noncompetitive. In this study on the effect of clomipramine, imipramine and some related drugs on serotonin uptake in human blood platelets in a protein-free medium, stress is laid on the use of an adequate blind value and correction for rapid decrease in substrate concentration during the incubation. Pure competitive inhibition was found for imipramine and desmethylchlomipramine, with increased Michaelis' constant (Km) without change in maximal uptake rate (Vmax). Clomipramine, however, and to a lesser degree the new compound citalopram (Lu 10-171), also reduces Vmax) indicating a mixed competitive and noncompetitive inhibitory effect event at extremely low concentrations (in the order of 10-9-10-8 M). The noncompetitive component of the clomipramine inhibition is not significantly influenced by increasing the period of preincubation, by varying pH, or by increasing the concentration of potassium. Contrary to desmethylclomipramine, however, clomipramine seems to interfere with the effect of chloride in the uptake process, by blocking the otherwise stimulatory effect of higher concentrations of this anion. © 1979 Springer-Verlag.