Immune hemolytic anemia caused by sensitivity to a metabolite of etodolac,a nonsteroidal anti-inflammatory drug

BACKGROUND: Immune hemolytic anemia can be caused by sensitivity to many di fferent drugs. In some instances, the sensitizing compound can be identifie d by in vitro testing, but results are often negative. One reason for this is that a drug metabolite formed in vivo can be the sensitizing agent, but the responsible metabolites have rarely been identified at a chemical level . This report describes a patient who developed severe, Coombs-positive hem olytic anemia on two occasions after taking the nonsteroidal anti-inflammat ory drug etodolac. Studies were performed to characterize etodolac metaboli tes to which this patient was sensitive. CASE REPORT: Serum was tested for antibody in the presence and absence of d rug using conventional methods and urine from individuals taking etodolac a s a source of drug metabolites. Urinary metabolites of etodolac were identi fied by high-pressure liquid chromatography analysis. Glucuronide conjugate s of etodolac and the 6-OH metabolite of etodolac were synthesized in a rat liver microsomal system to obtain reference standards. RESULTS: The patient's serum gave only trace (+/-) reactions with normal RB Cs in the presence of etodolac but reacted strongly (4+) in the presence of urine from an individual taking this drug. The active urinary metabolites were identified as etodolac glucuronide and 6-OH etodolac glucuronide. CONCLUSION: This patient appears to have experienced acute, severe immune h emolytic anemia on two occasions because of sensitivity to the glucuronides of etodolac and 6-OH etodolac. In patients suspected of having drug-induce d immune hemolytic anemia, RBC-reactive antibodies can sometimes be detecte d by using urine from an individual taking the implicated medication as the source of drug metabolites in in vitro reactions. For patients who present with acute immune hemolysis, a careful history of drug exposure should be taken, and, where indicated, confirmatory testing should be performed to id entify the sensitizing drug and prevent inadvertent reinduction of hemolysi s at a later time.