Controlled Biodistribution of Highly Lipophilic Drugs with Various Parenteral Formulations

Abstract

Lipid carrier systems are considered effective for targeting highly lipophilic drugs, but little systematic information about the effect of the physicochemical and pharmaceutical characteristics of drugs and formulations on their performance has been obtained. 3H-Retinoic acid and 14C-cholesteryl oleate with different lipophilicities (log PCoct = 6.6 and 18, respectively) were selected as model drugs and the potential of formulations such as oil in water (o/w) emulsion, micellar solution, and liposomes for controlling their biodistribution was demonstrated. After intravenous injection in mice, 3H-retinoic acid showed similar disposition profiles irrespective of formulation type, suggesting its rapid dissociation from carriers. 14C-Cholesteryl oleate with extremely high lipophilicity revealed widely varied disposition profiles reflecting the distribution patterns of carriers: micellar solution and liposomes showed large AUC values and low hepatic clearances, while the use of emulsion as a carrier resulted in rapid clearance from blood circulation into the liver. The results suggested that these formulations can be used as targeting carriers for lipophilic drugs which, however, should have a sufficiently high lipophilicity of about log PCoct 9-16.