DOPC

A few molecules have unexpectedly low permeability in 2% DOPC, not consistent with their octanol-water partition coefficients. Notably, metoprolol has a Pe value 10 times lower in 2% DOPC, compared to 10% egg lecithin. Also, prazosin Pe appears to be significantly lower in DOPC, compared to other lipids. 

The quality of the data collected from 2% DOPC membranes is unmatched by any other system we have explored. It s not uncommon to see interplate reproducibility 5% and intraplate even better than that (1-3% SD). As will be seen later, lipid model 1.0 does not predict GIT absorption as well as some of the newer pION models. However, this may not be the case when BBB models are explored in detail. 

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Figure 13.2 Fluorescence micrographs of DOPC multi-layer patterns fabricated by dip-pen nanolithography, (a) An array of 25 contiguous line features. Red color is from doped rhodamine-labeled lipid, (b) A higher magnification of the region highlighted by the white square in (a), (c) Two-component patterns containing two different dyes. Green color is from doped NBD-labeled lipid.

Avdeef, A., Tsinman, O. PAM PA -a drug absorption in vitro model 13. Chemical selectivity due to membrane hydrogen bonding in comho comparisons of HDM-, DOPC-, and DS-PAMPA models. Eur. J. Pharm. Set. 2006, 28, 43-50. 

Phospholipids are amphiphilic compoimds with high surface activity. They can significantly influence the physical properties of emulsions and foams used in the food industry. Rodriguez Patino et al. (2007) investigated structural, morphological, and surface rheology of dipalmitoylpho-sphatidylcholine (DPPC) and dioleoyl phosphatidylcholine (DOPC) monolayers at air-water interface. DPPC monolayers showed structural polymorphisms at the air-water interface as a function of surface pressure and the pH of the aqueous phase (Fig. 6.18). DOPC monolayers showed a... 

Lecithin (t g. DOPC) Desmopressin (dDAVP) Renin inhibitor (11214/03) Lypressin (LVP) Somatostatin (SRIF)... 

Figure 1. Phase diagrams of the systems M0-H20 (Adapted from ref. 1) and MO-DOPC-H20 (at 28 C, Adapted from ref. 2), respectively. G (gyroid) and D (diamond) are cubic phases with similar structures to the type shown schematically in the figure (Adapted from ref. 18).

Temperature 20°C, equilibrium dialysis, small unilamellar vesicles (DOPC), 0.1 M KC1 [382]. Centrifugation method (15 min, 150,000 g), brush-border membrane vesicles [433]. 

The system reported by Avdeef and co-workers [25-28,556-560] is an extension of the Roche approach, with several novel features described, including a way to assess membrane retention [25-28,556,557] and a way to quantify the effects of iso-pH [558] and gradient pH [559] conditions applied to ionizable molecules. A highly pure synthetic phospholipid, dioleoylphosphatidylcholine (DOPC), was initially used to coat the filters (2% wt/vol DOPC in dodecane). Other lipid mixtures were subsequently developed, and are described in detail in this chapter. 

These general observations have been confirmed in PAMPA measurements in our laboratory, using the 2% DOPC-dodecane lipid. With very lipophilic molecules, glycocholic acid added to the donor solution slightly reduced permeabilities, taurocholic acid increased permeabilities, but SLS arrested membrane transport altogether in several cases (especially cationic, surface-active drugs such as CPZ). 

Four neutral lipid models were explored at pH 7.4 (1) 2% wt/vol DOPC in dode-cane, (2) olive oil, (3) octanol, and (4) dodecane. Table 7.5 lists the effective permeabilities Pe, standard deviations (SDs), and membrane retentions of the 32 probe molecules (Table 7.4). The units of Pe and SD are 10 6 cm/s. Retentions are expressed as mole percentages. Figure 7.22a is a plot of log Pe versus log Kd (octanol-water apparent partition coefficients, pH 7.4) for filters loaded with 2% wt/vol DOPC in dodecane (model 1.0, hlled-circle symbols) and with phospholipid-free dodecane (model 4.0, open-circle symbols). The dashed line in the plot was calculated assuming a UWL permeability (see Section 7.7.6) Pu, 16 x 10-6 cm/s (a typical value in an unstirred 96-well microtiter plate assay), and Pe of 0.8 x 10-6 cm/s... 

It was thus interesting for us to examine the permeability and membrane retention properties of olive oil. As Table 7.5 shows, most of the Pe values for olive oil are less than or equal to those of 2% DOPC, with notable exceptions for instance, quinine is 4 times more permeable and progesterone is 16 times less permeable in olive oil than in DOPC. Both lipids show progesterone retention to be >80%, but quinine retention in olive oil is substantially greater than in DOPC. 

Figure 7.22b shows that hydrophilic molecules, those with log Kj < 1, are much more permeable in octanol than in olive oil. The same may be said in comparison to 2% DOPC and dodecane. Octanol appears to enhance the permeability of hydrophilic molecules, compared to that of DOPC, dodecane, and olive oil. This is dramatically evident in Fig. 7.7, and is confirmed in Figs. 7.8c and 7.22b. The mechanism is not precisely known, but it is reasonable to suspect a shuttle service may be provided by the water clusters in octanol-based PAMPA (perhaps like an inverted micelle equivalent of endocytosis). Thus, it appears that charged molecules can be substantially permeable in the octanol PAMPA. However, do charged molecules permeate phospholipid bilayers to any appreciable extent We will return to this question later, and will cite evidence at least for a partial answer. 

Membrane retention of lipophilic molecules is significantly increased in octanol, compared to 2% DOPC. Chlorpromazine and progesterone show R > 90% in octanol. Phenazopyridine, verapamil, promethazine, and imipramine show R > 70%. 

Figure 7.25 Membrane retention in 2%DOPC/dodecane-soaked filters versus dodecane-soaked filters.

Figure 7.25 is a plot of %R (2%DOPC in dodecane) versus %R (100% dode-cane). It shows that even 2% DOPC in dodecane can influence membrane retention to a considerable extent, compared to retentions observed in the absence of DOPC. Many molecules show retentions exceeding 70% in DOPC, under conditions where the retentions in dodecane are below 10%. However, it cannot be assumed that retention is always very low in dodecane, since several points in Fig. 7.25 are below the diagonal line, with values as high as 90% (chlorpromazine). 

Tables 7.6-7.8 list the Pe, SD, and %R of the 32 probe molecules in the thirteen new PAMPA lipid models, one of which is 2% DOPC assayed under sink conditions (model 1.1). The latter model served as a benchmark for assessing the effects of negative membrane charge.

Figure 7.26 Permeabilities with and without sink, 2% DOPC model.

DOPC with Dodecyicarboxyiic Acid under Sink Conditions... 

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