Bougie D, Johnson S T, Weitekamp L A, Aster R H
Blood Research Institute, The Blood Center of Southeastern Wisconsin Inc, Milwaukee 53201-2178, USA.
Blood. 1997 Jul 1;90(1):407-13.
A 75-year-old woman taking the nonsteroidal anti-inflammatory drug diclofenac (DCF) presented with acute Coombs-positive hemolytic anemia and subsequently developed renal failure. A drug-dependent antibody specific for red blood cells (RBCs) could not be demonstrated by in vitro testing with DCF. However, her serum was found to contain an IgM antibody that reacted strongly with RBCs in the presence of urine from any of four subjects who had ingested DCF. The active substance in urine was isolated, subjected to high-performance liquid chromatographic (HPLC) analysis, and found to be a glucuronide conjugate of a known DCF metabolite, 4'-hydroxydiclofenac (4'-OH DCF). Negative results were obtained with four other DCF metabolites. Two 4'-OH DCF glucuronides were synthesized in vitro using a liver microsomal system. One promoted agglutination of normal RBCs by the patient's serum and was identified as the glucuronide ester of 4'-OH DCF by proton nuclear magnetic resonance (NMR) analysis. Studies with a panel of RBCs showed that the patient's antibody reacted preferentially with the e antigen of the Rh system. Acute immune hemolytic anemia in this patient appears to have been caused by sensitization to DCF modified by 4' hydroxylation and glucuronidation. This is the first reported example of immune cytopenia caused by sensitivity to a glucuronide conjugate of a drug metabolite. Since glucuronidation is a common pathway of drug metabolism, studies of the frequency with which glucuronide derivatives of primary medications cause immune cytopenia seem warranted.
一名75岁服用非甾体抗炎药双氯芬酸（DCF）的女性出现急性抗人球蛋白试验阳性的溶血性贫血，随后发展为肾衰竭。体外使用DCF检测未发现针对红细胞（RBC）的药物依赖性抗体。然而，发现她的血清中含有一种IgM抗体，在摄入DCF的四名受试者中任何一人的尿液存在时，该抗体与RBC发生强烈反应。尿液中的活性物质被分离出来，进行高效液相色谱（HPLC）分析，发现是已知DCF代谢物4'-羟基双氯芬酸（4'-OH DCF）的葡萄糖醛酸共轭物。其他四种DCF代谢物检测结果为阴性。使用肝微粒体系统在体外合成了两种4'-OH DCF葡萄糖醛酸共轭物。其中一种促进了患者血清对正常RBC的凝集，并通过质子核磁共振（NMR）分析鉴定为4'-OH DCF的葡萄糖醛酸酯。对一组RBC的研究表明，患者的抗体优先与Rh系统的e抗原发生反应。该患者的急性免疫性溶血性贫血似乎是由对经4'羟基化和葡萄糖醛酸化修饰的DCF致敏引起的。这是首次报道的因对药物代谢物的葡萄糖醛酸共轭物敏感而导致免疫性血细胞减少的例子。由于葡萄糖醛酸化是药物代谢的常见途径，因此有必要研究主要药物的葡萄糖醛酸衍生物导致免疫性血细胞减少的频率。
