The Effect of the Membrane Fluidity on Pharmacokinetics for Lipid A Analog E5531

Abstract

The effect of the dispersing procedure on the aggregate size, membrane fluidity and the pharmacokinetics were evaluated for the lipid A analog E5531. The size of the aggregates prepared by the pH-jump method (pH 11.0 → 7.3) was decreased, reaching 20 nm with increasing dispersing time in 0.003 N NaOH (pH 11.0). The membrane fluidity of the aggregates increased with increasing dispersing time. When prepared by the normal dilution method (pH 7.3 → 7.3), the size of the aggregates remained constant at 150 nm and the membrane fluidity was smaller compared to samples prepared by the pH-jump method. Using samples with different degrees of hydration and different membrane fluidities prepared by the pH-jump method, the pharmacokinetics after intravenous administration into rats were evaluated, and the data obtained confirmed that the membrane fluidity was correlated with the pharmacokinetics in rat. In addition, E5531 vials were stable for 24 months at room temperature when used within 24 hr after reconstitution.