Antibody-mediated platelet destruction by quinine, quinidine, and their metabolites

Metabolites of quinine and quinidine, along with the parent compounds, were investigated for their ability to promote complement-mediated platelet destruction when combined with drug-dependent platelet antibodies from five patients with quinine- and quinidine-induced thrombocytopenia. In all, eight metabolites and four closely related structural analogues were studied. These included the desmethyl, 2'-oxo, 10,11-dihydroxy, N-oxide, N'-oxide, and diN,N'-oxide derivatives. When we used the cytotoxic chromium 51 release assay, the parent compounds were typically from 10 to greater than 300 times more effective than the corresponding metabolites and structural analogues in promoting antibody-mediated platelet lysis. Reaction patterns varied significantly among all antibodies and compounds studied, strengthening previous evidence that drug-dependent platelet antibodies are extremely heterogeneous in their reactions with platelets. Although most of the metabolites were much less potent than the parent compounds in promoting antibody-mediated platelet lysis, one quinidine-induced antibody was significantly inhibited in its quinidine-mediated lytic activity by the addition of desmethylquinidine, an essentially nonreactive metabolite with this particular antibody. These findings support the hypothesis that the native structures of quinine and quinidine are sufficient to provoke drug-dependent antibody formation and subsequent platelet destruction independently of their metabolites. They also suggest a possible protective role for some of these metabolites in certain individuals who are susceptible to this allergic drug reaction.