Metabolism of ticlopidine by activated neutrophils: Implications for ticlopidine-induced agranulocytosis

Ticlopidine is associated with a relatively high incidence of agranulocytos is and aplastic anemia. We have shown that other drugs associated with agra nulocytosis are metabolized to reactive metabolites by activated human neut rophils or by HOCl, which is the major oxidant produced by activated neutro phils. We set out to test the hypothesis that ticlopidine also fits this pa ttern and is oxidized to a reactive intermediate by activated neutrophils a nd HOCl. As much as 8% ticlopidine was metabolized by activated human neutr ophils to a dehydro-ticlopidine; however, this product did not account for all of the decrease in ticlopidine concentration. The oxidation products of ticlopidine by the combination of myeloperoxidase and hydrogen peroxide we re the same as those by HOCl: dehydrogenated ticlopidine and 2-chloroticlop idine. A neutrophil-derived reactive metabolite of ticlopidine was trapped with GSH and the same ticlopidine-GSH conjugate was found in both the myelo peroxidase and HOCl systems. Evidence for the identity of the reactive meta bolite was obtained by reaction of ticlopidine with HOCl in a flow reaction system coupled to a mass spectrometer. The mass spectra suggested that the reactive metabolite was a thiophene-S-chloride. We conclude that ticlopidi ne follows the same pattern of reactive metabolite formation by activated n eutrophils as other drugs associated with a high incidence of agranulocytos is, and the putative thiophene-S-chloride formed by activated neutrophils m ay be responsible for ticlopidine-induced agranulocytosis.