O/W lipid emulsions for parenteral drug delivery. IV. Changes in the pharmacokinetics and pharmacodynamics of a highly lipophilic drug, menatetrenone.

The pharmacokinetics and pharmacodynamics of antihemorrhagic vitamin, menatetrenone after intravenous injection as the lipid emulsion, were compared to those as the micellar solutions. Menatetrenone was selectively delivered to the liver, lungs and spleen and retained in them. Hepatic and splenetic concentration at 6 h (C6h) increased 21.6- and 27.1-fold, respectively, and the area under the tissue concentration-time curve up to 6 h (AUC(0-6h)) were 2.3- and 11.4-fold, respectively, when compared with its micellar solution. Antihemorrhagic effect of menatetrenone was assessed using warfarin-induced hypoprothrombinemic rats. The lipid emulsion of menatetrenone decreased the prothrombin time at 6h after intravenous injection more effectively than micellar solution. The dose response curves indicated that the efficacy of the lipid emulsion was 2.4-2.9 times that of a micellar solution, and this was correlated with AUC(0-6h) rather than C6h. The plasma level of clotting factor VII and the hepatic level of descarboxyprothrombin were also recovered more effectively, while no significant differences were noted between the two formulations for the plasma level of factor II or descarboxyprothrombin at the dose levels examined. Although selective delivery of menatetrenone in the liver by the lipid emulsion was due to phagocytosis by non-parenchymal cells, menatetrenone in the whole liver appeared to contribute to recovery from hypoprothrombinemia.