Distribution kinetics of salicylic acid in the dual-perfused rat liver preparation

The hepatic distribution kinetics of salicylic acid was determined using a single-pass dual hepatic artery (HA) and portal vein (PV) perfused in situ rat liver preparation. Bolus doses of [C-14]salicylic acid and of reference markers ([H-3]-water and [C-14]-sucrose) were injected in a random order i nto either the HA or PV and then, after an appropriate interval, into the a lternate vessel. The hepatic outflow profile of [C-14]salicylic acid displa yed a characteristic sharp peak followed by a slower eluting tail, whereas sucrose and water displayed unimodal outflow profiles. The biphasic outflow profile indicates that the hepatic distribution of salicylic acid is not i nstantaneous but is limited by a permeability barrier. The in situ permeabi lity surface area product for [C-14]salicylic acid was 3.35 +/- 0.26 ml/min /g for PV and 7.45 +/- 1.50 ml/min/g for HA administration. Furthermore, th eory dictates that hepatic uptake is influenced by both perfusion and perme ability if effective permeability surface area product/blood flow ratio lie s between the values of 0.06 and 7.0. Our estimates (3.0 for venous output and 6.7 for arterial input) indicate that hepatic uptake of salicylic acid is dependent on both perfusion and permeability. The volume terms were calc ulated using two different methods, standard and specific. Regardless of th e compound and method, the volume of distribution after arterial administra tion was larger than that after venous administration. In addition, a volum e of distribution approximately twice that of the total aqueous space (i.e, , HA, 2.23 +/- 0.13 versus 1.10 +/- 0.07 ml/g; PV, 1.72 +/- 0.16 versus 0.6 8 +/- 0.04 ml/g) implies that salicylic acid has a significant affinity for hepatic tissue. A similar tissue-to-perfusate partition coefficient associ ated with HA and PV input (5.40 +/- 0.38 versus 6.48 +/- 0.56) indicates th at affinity of salicylic acid for hepatic tissue is independent of the rout e of input.