Figure 7.30 (a) Permeabilities [for egg lecithin (Sigma) in dodecane] and (b) membrane retentions for a series of weak bases in various egg lecithin PAMPA models.

Without an artificial sink, the membrane retentions are very high, with many basic probe molecules showing R > 80%. With the imposed sink, many of the retentions dropped by as much as 50%. Furthermore, just 0.5% wt/vol cholesterol in dodecane (in addition to the sink) caused increased retention to drop by at least a further 10-30%. It was not possible to form stable cholesterol-containing lipid models under sink conditions with Avanti's egg lecithin; acceptor buffer solutions turned significantly turbid in the untenable model 13.1.

The peculiar depression of metoprolol and quinine permeabilities in 2% DOPC (model 1.0) was not seen in the egg lecithin models. Metoprolol and quinine were significantly more permeable in the lecithins, in line with expectations based on relative octanol-water lipophilicities and relative in vivo absorptions of p-blockers [593]. Soy Lecithin and the Effects of Phospholipid Concentrations

We explored the use of Avanti's ''20% lecithin soy lipid extract,'' dissolved at various concentrations in dodecane. This is not a highly purified grade, and contains 37% unspecified neutral lipids, most likely asymmetric triglycerides. We chose this grade because it contained negatively charged phospholipids, having a charged : zwitterionic lipid ratio about half way between that of BBM and BBB compositions (Table 7.1). Soy-based PAMPA lipid models have been prepared with (''20% extract'' grade) soy lecithin, 10-74% wt/vol in dodecane. These newly formulated lipids have net negative charge at pH 7.4, which further increases above pH 8, as the phosphatidic groups ionize (cf. ionization constants in Fig. 7.4). The inositol (predominant negatively charged lipid) content is 4 times higher in soy than in egg lecithin. However, when <74% phospholipid fractions are used, severe experimental problems arise. With lipophilic sample molecules, the use of concentrated phospholipid artificial membranes leads to two unwanted effects: (1) nearly complete membrane retention (90-100%) and (2) highly diminished permeability (indeterminate in some cases), both effects presumably due to excessive drug-membrane binding. These adverse effects are nearly eliminated by using an ionic surfactant to create a very strong sink condition in the acceptor compartment of the permeation cell. The negative charge on the micelles formed from the surfactant added to the acceptor compartment appears to play a stabilizing role.

Tables 7.12-7.14 list the pH 7.4 permeability and retention values of the probe series of drug substances, grouped as bases, acids, and neutral molecules. Figures 7.31a-c are graphs of the effective permeabilities with and without sink as a function of increasing soy content, beginning with 2% DOPC for a benchmark. Figures 7.32a-c are plots of the corresponding membrane retentions.

Most of the permeabilities of the bases decrease steadily as the phospholipid fraction increases. There are some significant exceptions. Metoprolol, which is only moderately permeable in the DOPC lipid, becomes appreciably permeable in 10% soy lecithin. But at the 68% soy level, this molecule also shows reduced transport.

The permeabilities of the acid examples rise with increasing phospholipid content, up to 20% lipid, with rank ordering preserved. Naproxen and ketoprofen

TABLE 7.12 Soy Lecithin in Dodecane PAMPA Models (No Sink), pH 7.4a

20% Soy

TABLE 7.12 Soy Lecithin in Dodecane PAMPA Models (No Sink), pH 7.4a

20% Soy

0 0

Post a comment