SALICYLAMIDE SULFATE CELL ENTRY IN PERFUSED-RAT-LIVER - A MULTIPLE-INDICATOR DILUTION STUDY

The hepatocellular entry of salicylamide sulfate conjugate, which bind s to both red blood cells and albumin, was examined with the multiple- indicator dilution technique in the perfused rat liver, with medium co ntaining both 20% red cells and 1% albumin (set A), red cells only (se t B), albumin only (set C) and neither red cells nor albumin (set D). [C-14]Salicylamide sulfate, Cr-51-labeled red cells (a vascular refere nce), I-125-labeled albumin, [H-3]sucrose or [Co-58] ethylenediaminete traacetic acid (EDTA) (high and low molecular weight interstitial refe rences, respectively) and (H2O)-H-3 or D2O (a cellular reference) were injected as a bolus into the portal vein. Among all sets of outflow d ata, the earliest immediate vascular recoveries for the [C-14] salicyl amide sulfate were lower than those for the vascular reference. For se ts A and B, the upslopes precessed those for the Co-58-EDTA curve, the n crossed over the Co-58-EDTA curves, with lower magnitude peaks occur ring at the same time as those for labeled albumin, whereas for sets C and D, in which red cells were absent, the upslopes of [C-14]salicyla mide sulfate lagged behind those for labeled albumin and [H-3]sucrose, reaching lower magnitude peaks coincidental in time with those for la beled sucrose. The precession of the [C-14]salicylamide sulfate curve over Co-58-EDTA or [H-3]sucrose in the presence (sets A and B) but not in the absence (sets C and D) of red cells and the absence of precess ion with albumin alone (set C) suggest that a red cell effect on the u pslope is more evident than that for albumin. For all experiments, the downslopes of the sulfate curve crossed over those of the labeled red cells, albumin, Co-58-EDTA and sucrose curves and then the water curv e at around the peak. The downslopes of the [C-14]salicylamide sulfate were similar to those for labeled water, suggesting rapid cellular in flux and efflux of salicylamide sulfate. Quantitative evaluation with a barrier-limited space-variable transit-time model for rapidly equili brating red cell and albumin binding accounted for the upslope effects on [C-14]salicylamide sulfate behavior and demonstrated its relativel y high liver cell permeability. Values for the unbound permeability su rface area product (0.029 to 0.036 ml sec-1 . gm-1) were not different , regardless of the presence or absence of red cells and albumin, and slightly exceeded values for hepatic blood flow (0.0186 +/- 0.0016 ml sec-1 . gm-1). Comparable influx (0.083 to 0.14 sec-1) and efflux (0.1 0 to 0.18 sec-1) coefficients were obtained, suggesting rapid cellular entry and efflux of salicylamide sulfate. The ratio of the derived ra te constants, which corresponds to the concentration ratio across the membrane, was 0.40 to 0.55. The findings contrast sharply with those f or acetaminophen sulfate, which enters liver cells poorly.