title: The disposition of aspirin and salicylic acid in the isolated perfused rat liver: the effect of normal and retrograde flow on availability and mean transit time.
abstract: The effect of changing the direction of perfusate flow from anterograde to retrograde on the disposition of acetylsalicylic acid (aspirin) and salicylic acid was studied in the single pass in-situ perfused rat liver. Mixtures of aspirin, [14C]salicylic acid and the inert reference solute [3H]sucrose were administered as boluses into the liver using red blood cell and albumin-free perfusate media at a flow rate of 30 mL min-1/liver. Hepatic availability (F), mean transit time (MTT) and normalized variance (CV2) for aspirin, preformed [14C]salicylic acid, salicylic acid produced from aspirin in the liver and [3H]sucrose were deduced from the outflow concentration profiles using statistical moment analysis. The values for F, MTT and CV2 for the solutes under anterograde perfusion were: aspirin (0.73 +/- 0.04, 15.13 +/- 2.01 s, 0.33 +/- 0.09, n = 5), preformed [14C]salicylic acid (1.05 +/- 0.06, n = 12, 43.19 +/- 2.21 s, 1.08 +/- 0.08, n = 5), salicylic acid from aspirin (0.33 +/- 0.05, 42.82 +/- 9.16 s, 0.73 +/- 0.10, n = 5) and [3H]sucrose (1.05 +/- 0.05, 16.88 +/- 0.77 s, 0.74 +/- 0.10, n = 5). The corresponding values for retrograde perfusions were: aspirin (0.73 +/- 0.02, 17.41 +/- 3.06 s, 0.32 +/- 0.09, n = 5), preformed [14C]salicylic acid (1.14 +/- 0.02, 44.42 +/- 3.16 s, 0.95 +/- 0.07, n = 5), salicylic acid from aspirin (0.33 +/- 0.09, 36.47 +/- 10.28 s, 0.58 +/- 0.05, n = 5) and sucrose (1.01 +/- 0.04, 18.08 +/- 1.61 s, 0.76 +/- 0.15, n = 5). No significant differences in F or MTT were apparent between anterograde and retrograde perfusions for all solutes. The MTT and CV2 data for [14C]salicylic acid and salicylic acid produced from aspirin is suggestive of a permeability limitation for salicylic acid transport.
authors.affiliation: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: G D
authors.initials: GD
authors.lastname: Mellick
authors.forename: M S
authors.initials: MS
authors.lastname: Roberts
mesh_terms: D000818:Animals; D001241:Aspirin / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D010477:Perfusion / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000378:metabolism*; D020156:Salicylic Acid; D013395:Sucrose / Q000378:metabolism
chemical_list: D012459:Salicylates; D013395:Sucrose; D020156:Salicylic Acid; D001241:Aspirin