Abstract

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 [¹⁴C]salicylic acid and of reference markers ([³H]-water and [¹⁴C]-sucrose) were injected in a random order into either the HA or PV and then, after an appropriate interval, into the alternate vessel. The hepatic outflow profile of [¹⁴C]salicylic acid displayed 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 instantaneous but is limited by a permeability barrier. The in situ permeability surface area product for [¹⁴C]salicylic acid was 3.35 ± 0.26 ml/min/g for PV and 7.45 ± 1.50 ml/min/g for HA administration. Furthermore, theory dictates that hepatic uptake is influenced by both perfusion and permeability if effective permeability surface area product/blood flow ratio lies 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 calculated using two different methods, standard and specific. Regardless of the compound and method, the volume of distribution after arterial administration was larger than that after venous administration. In addition, a volume 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 0.68 ± 0.04 ml/g) implies that salicylic acid has a significant affinity for hepatic tissue. A similar tissue-to-perfusate partition coefficient associated with HA and PV input (5.40 ± 0.38 versus 6.48 ± 0.56) indicates that affinity of salicylic acid for hepatic tissue is independent of the route of input.