Poloxamer 407 increases the recovery of paracetamol in the isolated perfused rat liver.
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.
Mitchell
Sarah J
SJ
Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, Australia. smitchell@med.usyd.edu.au
Huizer-Pajkos
Aniko
A
Cogger
Victoria C
VC
McLachlan
Andrew J
AJ
Le Couteur
David G
DG
Hilmer
Sarah N
SN
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
D018712:Analgesics, Non-Narcotic; D013501:Surface-Active Agents; D020442:Poloxamer; D000082:Acetaminophen