Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis.
Ticlopidine is associated with a relatively high incidence of agranulocytosis and aplastic anemia. We have shown that other drugs associated with agranulocytosis are metabolized to reactive metabolites by activated human neutrophils or by HOCl, which is the major oxidant produced by activated neutrophils. We set out to test the hypothesis that ticlopidine also fits this pattern and is oxidized to a reactive intermediate by activated neutrophils and HOCl. As much as 8% ticlopidine was metabolized by activated human neutrophils 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 were the same as those by HOCl: dehydrogenated ticlopidine and 2-chloroticlopidine. A neutrophil-derived reactive metabolite of ticlopidine was trapped with GSH and the same ticlopidine-GSH conjugate was found in both the myeloperoxidase and HOCl systems. Evidence for the identity of the reactive metabolite 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 ticlopidine follows the same pattern of reactive metabolite formation by activated neutrophils as other drugs associated with a high incidence of agranulocytosis, and the putative thiophene-S-chloride formed by activated neutrophils may be responsible for ticlopidine-induced agranulocytosis.
Liu
Z C
ZC
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Uetrecht
J P
JP
D000380:Agranulocytosis / Q000139:chemically induced*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction; D013988:Ticlopidine / Q000009:adverse effects / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006997:Hypochlorous Acid; D005978:Glutathione; D013988:Ticlopidine