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The effect of aging on acetaminophen pharmacokinetics, toxicity and Nrf2 in Fischer 344 rats.

The journals of gerontology. Series A, Biological sciences and medical sciences (2013-07-19)
John Mach, Aniko Huizer-Pajkos, Victoria C Cogger, Catriona McKenzie, David G Le Couteur, Brett E Jones, Rafael de Cabo, Sarah N Hilmer
ABSTRACT

We investigated the effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, IgG fraction of antiserum, buffered aqueous solution
Paracetamol, European Pharmacopoeia (EP) Reference Standard
Supelco
Paracetamol β-D-glucuronide, analytical standard
Supelco
Acetaminophen, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Acetaminophen, analytical standard
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Supelco
Acetaminophen solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
USP
Acetaminophen, United States Pharmacopeia (USP) Reference Standard