THE EFFECT OF IONIC-STRENGTH ON LIPOSOME-BUFFER AND 1-OCTANOL-BUFFER DISTRIBUTION COEFFICIENTS

The distribution of salmeterol and proxicromil between unilamellar ves icles 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 ve sicles induces a surface charge, which causes the observed membrane di stribution coefficient (DOmemobs) to vary significantly with bound com pound 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 n eutral 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 involvi ng the extraction of ion pairs. This study highlights the experimental difficulty in determining concentration-independent liposome distribu tion coefficients of ionized lipophilic compounds and describes when d eviations will be significant and how observed values may be corrected for such effects. The general effect of ionic strength on membrane-bu ffer distribution and 1-octanol-buffer distribution is discussed with particular reference to the very different propensity for ion pair for mation shown by the two systems, and the most suitable experimental co nditions that should be used with each system.