The effect of divalent cations on the membrane properties and pharmacokinetics in rat of the lipid A analogue E5531.
To obtain information on the effects of Ca2+ on the membrane properties of the lipid A analogue E5531, we have determined the aggregate size, zeta potential, membrane fluidity, micropolarity and permeability of the E5531 membrane as a function of Ca2+ levels. Within the molar ratios of [Ca2+]/[E5531] = 1 and 3, Ca2+ increased the zeta potential of the E5531 membrane but had no effect on aggregate size (approximately 20 nm). Within the above ratios, Ca2+ decreased the membrane fluidity, as measured by micropolarity of E5531 and increased the phase transition temperature. The pharmacokinetics in rats for these samples with different membrane fluidity, prepared by changing the pre-dose formulation concentration of Ca2+, was determined and a correlation between membrane fluidity and pharmacokinetics was clearly observed. It thus appears that Ca2+ effects the membrane fluidity of E5531 as well as its pharmacokinetics in rats.
Asai
Y
Y
Formulation Research Laboratory, Kawashima, Eisai Co., Ltd, Gifu, Japan.
Sano
Y
Y
Kikuchi
K
K
Iwamoto
K
K
Watanabe
S
S
D000818:Animals; D019540:Area Under Curve; D002118:Calcium / Q000494:pharmacology*; D002413:Cations, Divalent; D002449:Cell Aggregation / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006207:Half-Life; D007275:Injections, Intravenous; D008050:Lipid A / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008560:Membrane Fluidity / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects*; D051381:Rats
D002413:Cations, Divalent; D008050:Lipid A; C092845:E 5531; D002118:Calcium