<b>Influences of Long-Term, High-Dose Acetaminophen Administration on Liver Function Markers in Healthy Japanese Adults </b>

Abstract

Background : Acetaminophen is widely used as an analgesic and antipyretic ; however, acetaminophen overdose is known to cause hepatic injury. However, minor and self-limiting alanine aminotransferase(ALT)elevation unrelated to hepatic injury is occasionally observed in individuals receiving high-dose acetaminophen. The aim of this study was to evaluate the changes in liver function markers induced by long-term, highdose acetaminophen administration. Methods : Acetaminophen (3000 mg／day) or placebo was repeatedly administered to 242 healthy Japanese adults for 28 days. Plasma samples collected on Day 1 were used to measure the pharmacokinetics of acetaminophen. Liver function was monitored in terms of aspartate aminotransferase(AST), ALT, alkaline phosphatase (ALP), total bilirubin (T-Bil), and high mobility group box 1(HMGB-1)levels for 35 days, from the day of the first dose. Subjects were withdrawn from the study if their AST, ALT, or ALP levels exceeded twice the respective upper limit of normal(2×ULN). Results : From a total of 242 subjects, 202 and 40 subjects were assigned to the acetaminophen group and the placebo group, respectively. Twelve subjects in the acetaminophen group (6.0％) were withdrawn owing to ALT elevation over 2× ULN ; no subjects were withdrawn from the placebo group. During the study period, ALT was higher in the acetaminophen group than in the placebo group, and increased from Day 7 to 14 after the start of administration. However, no evidence of hepatic injury owing to acetaminophen was observed, and the ALT elevation was attenuated after Day 14. Moreover, no correlation was observed between maximum ALT and levels of HMGB-1, a novel biomarker candidate for hepatic injury, during the study period. These findings led us to conclude that the ALT elevation was not caused by hepatic injury. Conclusion : ALT elevation ＞2×ULN was observed in 6.0％ of subjects in the acetaminophen group. However, no subjects developed hepatic injury, and ALT levels started to return to the normal values even during continued administration. The phenomenon of adaptation may be involved in these changes.

Real‐World Hepatic Safety of Oral Acetaminophen Versus Loxoprofen/Celecoxib: Using a Nationwide Electronic Medical Record Database

“…14 The non-inferiority of APAP to loxoprofen and celecoxib was demonstrated by the secondary end point of the incidence rate of elevated ALT in this study. However, elevated ALT levels do not directly indicate drug-induced liver injury, 32 and liver injury should be diagnosed based on ALT levels and other significant clinical findings. 33 Therefore, it is important to avoid overinterpreting this secondary outcome.…”