title: Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity.
abstract: Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.
authors.affiliation: Department of Pediatrics, Little Rock, AR, United States.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Milesi-Hallé
authors.forename: Susan M
authors.initials: SM
authors.lastname: Abdel-Rahman
authors.forename: Aliza
authors.initials: A
authors.lastname: Brown
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McCullough
authors.forename: Lynda
authors.initials: L
authors.lastname: Letzig
authors.forename: Jack A
authors.initials: JA
authors.lastname: Hinson
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000111:Acetylcysteine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D004396:Coloring Agents / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D007208:Indocyanine Green / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors
chemical_list: D000931:Antidotes; D004396:Coloring Agents; D000082:Acetaminophen; D000410:Alanine Transaminase; D007208:Indocyanine Green; D000111:Acetylcysteine