Zc. Liu et Jp. Uetrecht, Metabolism of ticlopidine by activated neutrophils: Implications for ticlopidine-induced agranulocytosis, DRUG META D, 28(7), 2000, pp. 726-730
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.