title: Poloxamer 407 increases the recovery of paracetamol in the isolated perfused rat liver.
abstract: The role of the fenestrated liver sinusoidal endothelial cells (LSECs) in the hepatic disposition of paracetamol was investigated in isolated perfused livers from rats treated with poloxamer 407 (P407), a surfactant that causes extensive defenestration of the LSECs. Bolus doses containing tracer amounts of (14)C-paracetamol and reference markers (Evans Blue, (3)H-sucrose) were injected into control rats and rats that had been administered P407 via intra-peritoneal injection 24  h prior to experimentation. Scanning electron microscopy confirmed a reduced number of fenestrations in rats treated with P407. The recovery of paracetamol was significantly increased in P407 rats compared to controls (0.72 ± 0.07 P407 vs. 0.67 ± 0.04 control, p < 0.05) and the volume of distribution of paracetamol as a fraction of the sucrose volume was significantly reduced. The permeability-surface area (PS) product for the transfer of paracetamol across the LSECs was also reduced in the P407 rats (0.032 ± 0.009 P407 vs. 0.043 ± 0.007  mL/s/g controls, p < 0.05). P407 treatment resulted in increased recovery and decreased PS product of paracetamol following a single pass through the isolated perfused liver. This is consistent with exclusion of paracetamol from the space of Disse due to defenestration of the LSECs.
authors.affiliation: Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, Australia. smitchell@med.usyd.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: Sarah N
authors.initials: SN
authors.lastname: Hilmer
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008855:Microscopy, Electron, Scanning; D008954:Models, Biological; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D020442:Poloxamer / Q000633:toxicity; D011865:Radioisotope Dilution Technique; D051381:Rats; D011916:Rats, Inbred F344; D013499:Surface Properties / Q000187:drug effects; D013501:Surface-Active Agents / Q000633:toxicity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D013501:Surface-Active Agents; D020442:Poloxamer; D000082:Acetaminophen