Abstract

Cyproheptadine, an antihistaminic antiserotonergic agent, inhibits platelet aggregation. This study describes the accumulation, in vitro, of ¹⁴C-cyproheptadine by the human platelet and inhibition thereof by phenothiazines and tricyclic antidepressants. Platelets were incubated at 37°C for various times in Ca⁺⁺- and Mg⁺⁺-free Krebs-Ringer-bicarbonate buffer under O₂-CO₂ (95:5, v/v). When incubated for two minutes with ¹⁴C-cyproheptadline, 0.5 mM to 1.4 µM, platelets accumulated radioactivity with gradients ([I]/ [O]) of 65 to 290, respectively. At all concentrations of the drug, no additional uptake occurred upon increasing incubations to 60 minutes. Under all circumstances, > 98% of platelet-associated radioactivity migrated with anthentic cyproheptadine on thin layers of silicic acid. At an initial concentration of 0.014 mM ¹⁴C-cyproheptadine and with 10 minute incubations, 50% suppression of the radioactivity gradient occurred with chlorpromazine (0.13 mM), phenotimiazine (0.13 mM), promethazine (0.15 mM), amtriptyline (0.23 mM), desipramine (0.20 mM), imipramine (0.16 mM), nortriptyline (0.10 mM) and protriptyline (0.13 mM). Several other basic compounds, including histamine and serotonin, and metabolic inhibitors were not inhibitory. The lack of effect by incubation in the cold or by metabolic inhibitors, the rapidity of uptake of ¹⁴C-cyproheptadine and the localization of most of the radioactivity in the 120,000 x g fraction from platelet homogenate indicate that accumulation is mainly due to binding of cyproheptadine to the platelet membrane rather timan active transport. Binding of the drug to platelets incubated in plasma Suggests this phenomenon may also occur in vivo. ¹⁴C-cyproheptadine is not metabolized by the platelet. The possible relationship between the binding of cyproheptadine to the platelet and inhibition of aggregation is discussed.