Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system

Abstract

The hepatic disposition properties of [ 3h]retinoic acid with moderate lipophilicity and having a logarithm of the n-octanol/water partition coefficient (log PC oct) of 6.61 were analyzed in comparison with those of lipid carrier systems labeled by [ 14c]cholesteryl oleate in an in situ single-pass rat liver perfusion experimental system. Oil-in-water (o/w) type emulsions with mean diameters of 252 and 85 nm, liposomes with a diameter of 122 nm and a HCO-60 micellar solution were tested as lipid carriers. During a single passage through the liver, the large emulsion showed marked uptake of [ 14C]cholesteryl oleate incorporated in oil droplets, while the other three carriers showed almost complete recovery in the venous outflow, suggesting their ‘stealthy’ nature. The outflow patterns of [ 3H]retinoic acid injected with lipid carriers were analyzed on the basis of moment analysis assuming first-order release from carrier particles, with the data for [ 3H]retinoic acid injected in the form of an aqueous solution. Injection with micellar solution and the small emulsion demonstrated a rapid rate of release of [ 3H]retinoic acid, however, the large emulsion and liposomes showed considerable retention and delivered [ 3H]retinoic acid to the liver non-parenchymal cells and to the venous outflow side, respectively, stably entrapping it.