SUN-153 ACCUMULATION OF ACETAMINOPHEN METABOLITES EXERTS KIDNEY PROTECTIVE EFFECT IN RENAL FAILURE RAT MODEL

Abstract

Acetaminophen (APAP) is recommended preferential use in pain management of chronic kidney disease (CKD) patients owing to fewer side effects in clinical dose. Although it is highly safe drug, usefulness of APAP is not consistent during long-term dosing in renal failure. So far, we have obtained the results that repeated administration of APAP does not worsen renal function in the adenine-induced renal failure model rats, suggesting that APAP might have antioxidant effect. In this study, we focused on the antioxidant effect of APAP and its metabolites, evaluated association between long-term APAP administration and renal function or oxidative stress in vivo and in vitro. first, we carried out daily oral administration of APAP (150 or 750 mg / kg) for 12 weeks against 5/6 nephrectomy (Nx) renal failure model rat, and evaluated the biochemical parameters, oxidative stress markers, as well as the drug concentration of APAP and its metabolites. We also examined the antioxidant capacity of APAP using HUVEC and EPR in vitro. Long-term administration of APAP did not induce further renal dysfunction. Furthermore, the APAP treated group significant inhibited the production of plasma 8-OHdG. Also, results of DHE staining of the renal tissue indicated that an oxidative stress was suppressed by APAP administration. Interestingly, APAP metabolites, normally excreted into urine, accumulated in the plasma and renal tissue. The antioxidant effect of these metabolites was evaluated in vascular endothelial cells (HUVEC), APAP metabolites showed a significant ROS inhibitory effect of ROS induced by uremic toxin indoxyl sulfate. From these results, it is suggested that APAP metabolites accumulated by renal failure might exhibit renal protective effect due to a part its antioxidant capacity. in the Future by monitoring of APAP metabolites by TDM, it is possible to establish a more effective method of APAP administration, the efficacy of a new antioxidant effect of APAP metabolites can be expected.