Chloramphenicol oxamylethanolamine as an end product of chloramphenicol metabolism in rat and humans: evidence for the formation of a phospholipid adduct.

Abstract

Chloramphenicol (CP) has been implicated as, although not proven to be, a causative agent of aplastic anemia in humans. Recent studies from our laboratory have presented evidence that CP-oxamylethanolamine was an end product of CP biotransformation in birds. Because this novel metabolic pathway has never been reported in other species, we have now expanded these investigations to rat and humans. [3H]CP was administered po (10 mg/kg) to adult male Wistar rats and to a human volunteer. Urine was collected and analyzed by HPLC and GC-MS for CP metabolite determination. In rat, the two most important metabolites in 0-24 h urine were CP-base and CP-acetylarylamine which together accounted for about 50% of the ingested radioactivity. The remainder was due to unchanged CP, CP-oxamic acid, CP-alcohol, CP-glucuronide, and CP-oxamylethanolamine. The presence of these end products was also demonstrated in man. CP-oxamylethanolamine represented 0.74% and 1.37% of the ingested radioactivity in rat and human urine samples, respectively. CP-oxamylethanolamine formation was confirmed in vitro with isolated rat hepatocytes, suggesting the involvement of liver in the production of this metabolite. The origin of CP-oxamylethanolamine has been investigated with the use of hepatic liver microsomes from phenobarbital-treated rats. The incubation of [3H]CP with this subcellular fraction led to the binding of a radiolabeled compound to the microsomal lipids, whereas no binding occurred when CP-oxamic acid was incubated with the microsomes. Enzymatic hydrolysis of the microsome lipid fraction with phospholipase D from Streptomyces chromofuscus released CP-oxamylethanolamine.(ABSTRACT TRUNCATED AT 250 WORDS)