title: Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats.
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.
authors.affiliation: Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia. sarah.mitchell@sydney.edu.au
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.forename: Aniko
authors.initials: A
authors.lastname: Huizer-Pajkos
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.forename: Brett
authors.initials: B
authors.lastname: Jones
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics*; D000375:Aging; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D000818:Animals; D058633:Antipyretics / Q000493:pharmacokinetics*; D004727:Endothelium / Q000378:metabolism; D007201:Indicator Dilution Techniques; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008855:Microscopy, Electron, Scanning; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D000082:Acetaminophen