| Popis: |
In many cases of drug-induced immunologic thrombocytopenia (DITP), a metabolite, rather than the native drug, is suspected of provoking the destructive drug-dependent antibodies (DDAB) responsible for this severe hemorrhagic disorder. However, this has not previously been investigated for Qn- and Qd-DDAB. We report evidence that the native drugs, and not their metabolites, are the provocative agents in Qn and Qd DITP. Reactions of Qn- and Qd-DDAB with platelets were studied with the native drugs and four of their metabolites: the N-oxide and 10,11-diol derivatives (quinuclidine ring modifications), the des-methyl derivatives (aromatic quinoline ring modification), and 2'-quininone and 2'-quinidinone (2'-oxo derivatives) (also quinoline ring modifications on Qn and Qd, respectively). Five antibodies were studied:two Group 1 DDAB (specific for compounds with native configuration at asymmetric carbon positions), two Group 2 DDAB (similar to Group 1 DDAB but also known to require the methoxy group on the quinuclidine ring for full activity), and one Group 3 DDAB (reactive with the native drug, its stereoisomer, and several nonmetabolic analogs of both compounds) . Using a complement-dependent 51Cr-lysis assay, the reactions of all DDAB with platelets and the four metabolites were similar to 100-fold weaker when compared to reactions obtained with the native drug, with these exceptions:Group 2 DDAB failed to react with the desmethyl and 2'-oxo metabolites and the Group 3 DDAB failed to react with 2'-oxo Qd. This observation shows that the activity of certain DDAB is critically dependent on the native quinoline ring structure. Importantly, none of the DDAB reacted more strongly with any of the metabolites tested when compared with reactions in the presence of the native drug. These findings indicate that DDAB react with platelets preferentially in the presence of the unaltered Qn and Qd molecules and suggest that, while the role of metabolites cannot be entirely ruled out, the native structure of the drug molecule is sufficient to stimulate production of the antibodies responsible for DITP. |
