Metabolism and excretion of a glutathione conjugate of acetaminophen in the isolated perfused rat kidney

Acetaminophen-glutathione (APAP-GSH) is the initial sulfur-con-taming metabolite of APAP produced by the liver. However, little, if any, APAP-GSH is found in the urine of intact animals. Rather, the cystelne(APAP-CYS)and N-acetylcysteine (APAP-NAC) con-jugates are the predominant sulfur-containing metabolites of APAP excreted in the unne. To define more precisely the role of the kidney in total body disposition of APAP, the metabolism and excretion of each of these metabolites was quantified in the isolated perfused rat kidney (IPK). With perfusate concentrations of 0.031, 0.125 and 0.250 mM APAP-GSH, the IPK metabolized APAP-GSH to APAP-CYS rapidly. Further metabolism of APAP-CYS to APAP-NAC proceeded at a much slower rate. Conse-quently, at 0.031 mM APAP-GSH, negligible amounts of APAP-CYS were found in the urine. However, as the concentration of APAP-GSH was increased so did the excretion of APAP-CYS. In contrast, the excretion of APAP-NAC did not exhibit depend-ence on APAP-GSH concentration. APAP-NAC was excreted by a probenecid sensitive transport mechanism whereas APAP-CYS excretion appeared to be related only to glomerular filtra-tion. In addition, the disappearance of APAP-GSH was much greater than could be accounted for by glomerular filtration. These data indicate that the IPK is an effective model for the study of metabolism and excretion of xenobiotics that have undergone conjugation with GSH. APAP, commonly known as acetaminophen or paracetamol, is an antipyretic analgesic which in human overdose situations has produced a characteristic, and sometimes fatal, masaive centrilobular hepatic necrosis and acute renal failure (Boye