Pharmacokinetic Of Acetaminophen And Its Regulation Of Circadian Rhythms Of Liver Toxicity

Acetaminophen (APAP) is widely used as analgesic and antipyretic drugs. It is generally considered a safe drug at normal therapeutic dose but when taken in excess, it caused liver failure and death. It was reported that APAP induced hepatotoxicity showed temporal variation in which the mechanism remains unclear. In this paper, we investigated the impact of clock gene on APAP induced hepatic injury and its pharmacokinetics using mPer2 knockout mice.Wide type (WT) and mPer2-/-mice were received intraperitoneal injection of APAP at the dose of 300mg/kg at 08:00 and 20:00, respectively. Serum aminotransferase activity and histological data revealed that APAP induced liver damage in WT and mPer2-/-mice showed markedly enhanced at 20:00 compared with that at 08:00, meanwhile, mPer2 null mice displayed much less severe liver injury when the injection time was 20:00.The hepatic circadian expression of mPer2 revealed that its mRNA level was weak at 08:00 but reached peak expression during 12h at 20:00 in WT mice. These results show that the gene expression of mPer2 was related with the APAP induced hepatotoxicity.In pharmacokinetic analysis, WT and mPer2-/- mice were received intraperitoneal injection of APAP at the dose of 300mg/kg at 08:00 and 20:00. Serum APAP concentration was measured by HPLC. Pharmacokinetic parameters showed that total clearance (CL) was markedly decreased in mPer2-/- mice than WT mice. Therefore, clock gene Per2 deficient lower the CL of APAP in mice. In addition, the CL of APAP in WT mice was dramatically increased at 20:00 compared with 08:00. The results show that mPer2 may function in diurnal variation of the CL of APAP in WT mice.Finally, we studied the effect of Mg2+on APAP induced hepatotoxicity. C57B/6L mice were divided randomly into three groups, which were feed control food, low Mg2+-contained food and high Mg2+-contained food, respectively for 10 days. Then APAP was injected. Serum aminotransferase activity and histological data revealed that mice from Mg2+contained group showed markedly less severe liver damage. Therefore, this data suggested that Mg2+could decrease APAP induced hepatotoxicity.