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

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, [C-14]salicylic acid and the inert reference solute [H-3]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 [C-14]salicylic acid, salicylic acid produced from aspirin in the liver and [H-3]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 +/- 201 s, 0.33 +/- 0.09, n = 5), preformed [C-14]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 [H-3]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 [C-14]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 14 solutes. The MTT and CV2 data for [C-14]salicylic acid and salicylic acid produced from aspirin is suggestive of a permeability limitation for salicylic acid transport.