Partitioning into Charged Liposomes

With liposome partitioning, however, the rule slips to diff 1-2. This means SIP partitioning starts at about pH 8.5 for weak bases whose pKa values are near 9.5 (e.g., Figs. 5.7b, 5.11). So, all who published anomalous values of log P em may need to get out their slide rules 1429—4-321 (What we know now was not known then.) 

Since the FFA is an anion pH 7 and propranolol a cation pH 9, there is a window of opportunity between pH 7 and 9 for electrostatic attraction of propranolol into the membrane phase, as indicated in Fig. 5.11. Note how similar the curve shapes in Fig. 5.11 are to some of the curves in Fig. 4.6b. 

Ionizable molecules embedded in the surfaces of lipids, such as octanol (see Fig. 2.8), liposomes (see Fig. 5.2), or micelles, will have their apparent pKa values shifted. With neutral lipids, the pKa of an acid increases and the pKa of a base decreases. This is due to the effect of the decreased dielectric constant in the interfacial zone, as we have already discussed in various sections. 

An additional (electrostatic) shift occurs if the lipid vesicles or micelles have a charged surface, according to the expression suitable for monoprotic acids and bases 

TABLE 5.3 Critically Selected Experimental Liposome-Water Partition Coefficients 

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The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

Dithiocarbamates and xanthates form particularly stable, neutral complexes with Cu(II), Cd(II) (and also Ni, Hg, Pb), which are membrane permeable and increase the apparent bioaccumulation of these metals [13]. In the series of sulfoxine, oxine, and chloroxine, the hydrophobicity of the neutral and the charged form, as well as of the Cu complex, increases. While the sulfoxine is not hydrophobic and does not modulate copper toxicity [220], the Cu-oxine complex is hydrophobic with an octanol-water partition constant, log Kok, of 1.7 [221] or 2.6 [222]. Chloroxine can be assumed to be even more hydrophobic, but so far its influence on uptake and toxicity has not been investigated. Uptake of Cu2+ into unilamellar liposomes was increased in the presence of 8-hydroxy-chinoline, and decreased again after adding HA [223],... 

For the neutral form of 13 bases, again a very poor correlation between partitioning into octanol and liposomes was observed. The range found for the partition coefficients was 2.0 to 6.0 in octanol and +1.0 to < 5.0 in the liposomal system (-2 is the observable minimum according to the authors). Poor correlations were also found for the cationic forms of the bases (r2 = 0.49). Generally, the differences (log Poct.-log Psuv) for the neutral forms are smaller than the differences observed for the charged species. 

The larger partition coefficient into lipids is because only the neutral form can efficiently partition into octanol. Ordered phospholipid bilayers can, however, take up both forms neutral and charged. The influence of anionic and cationic charge on the ability of amphiphilic drugs to partition and bind to DPPC liposomes was investigat-... 

The studies on phospholipid bilayers with defined amounts of charged component are helpful to explain the partition characteristics in biological membranes. Liposome water partition data of propranolol in lipids from kidney epithelial cells (a common model system in pharmaceutical sciences for the uptake into the gastrointestinal tract) have been successfully described with partition models developed for pure bilayers or defined mixtures [159]. Since lipophilic cations and anions can be used as probes for the membrane potential, their interaction with microbial and mitochondrial membranes has been studied... 

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