The Effect of lonic Strength on Liposome–Buffer and 1-Octanol–Buffer Distribution Coefficients

Abstract

The distribution of salmeterol and proxicromil between unilamellar vesicles of dioleoylphosphatidylcholine (DOPC) and aqueous buffer at pH 7.4 has been studied, using an ultrafiltration method, as a function of compound concentration, DOPC concentration, and buffer ionic strength. The binding of these ionized lipophilic compounds to neutral DOPC vesicles induces a surface charge, which causes the observed membrane distribution coefficient D(mem)obs to vary significantly with bound compound to DOPC ratio and with ionic strength. This variability is shown to be well-described with use of the Gouy-Chapman theory of the ionic double layer and is contrasted with the ideal behavior shown by the neutral compound clofibrate. Increasing ionic strength is also shown to increase the observed 1-octanol-buffer distribution coefficients D(o/w)obs of proxicromil but through a very different mechanism involving the extraction of ion pairs. This study highlights the experimental difficulty in determining concentration-independent liposome distribution coefficients of ionized lipophilic compounds and describes when deviations will be significant and how observed values may be corrected for such effects. The general effect of ionic strength on membrane-buffer distribution and 1-octanol-buffer distribution is discussed with particular reference to the very different propensity for ion pair formation shown by the two systems, and the most suitable experimental conditions that should be used with each system.