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Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats.

Authors
  • Mitchell, Sarah J1
  • Huizer-Pajkos, Aniko
  • Cogger, Victoria C
  • McLachlan, Andrew J
  • Le Couteur, David G
  • Jones, Brett
  • de Cabo, Rafael
  • Hilmer, Sarah N
  • 1 Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia. [email protected] , (Australia)
Type
Published Article
Journal
The journals of gerontology. Series A, Biological sciences and medical sciences
Publication Date
Apr 01, 2011
Volume
66
Issue
4
Pages
400–408
Identifiers
DOI: 10.1093/gerona/glq221
PMID: 21300741
Source
Medline
License
Unknown

Abstract

We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer (14)C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ± 0.04, old; 0.59 ± 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k(1) (0.34 ± 0.10 s(-1), old; 0.61 ± 0.38 s(-1), young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ± 0.006 mL/s/g, old; 0.048 ± 0.014 mL/s/g, young; p < .005). There was no difference in k(3), the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver.

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