Membranes Octanol data

Our first exploration of property space was focused on acetylcholine. This molecule was chosen for its interesting structure, major biological role, and the abundant data available on its conformational properties [15]. The behavior of acetylcholine was analyzed by MD simulations in vacuum, in isotropic media (water and chloroform) [16] and in an anisotropic medium, i.e. a membrane model [17]. Hydrated n-octanol (Imol water/4mol octanol) was also used to represent a medium structurally intermediate between a membrane and the isotropic solvents [17]. 

As chronicled by Dearden [21], the association of compound lipophilicity with membrane penetration was first implied by Overton and Meyer more than a century ago. To enhance this understanding, lipophilicity measurements were initially performed using a variety of lipid phases [22], while the comprehensive review by Hansch et al. [23], with extensive data from literature and their own measurements, lent further support to the now accepted wide use of the octanol-water solvent system. 

Potential differences between the nitrobenzene and aqueous phases at the interfaces in the presence [Fig. 2(B)] and absence of surfactant (C) were measured simultaneously. KCl salt bridges were inserted into the octanol phase to monitor potential. Oscillation measurement data across the nitrobenzene membrane are given in Fig. 2(A) for comparison. The oscillation mode in Fig. 2(C) is virtually the same as that in (A) with respect to oscillatory period and amplitude but quite different with that in (B). Although the potential across the nitrobenzene membrane (A) was not recorded simultaneously with that between nitrobenzene-water phases (B) and (C) but successively, it was noted that the algebraic sum of (B) and (C) should be essentially the same as (A). This is an indication that potential oscillation across the nitrobenzene membrane is likely generated at the interface between the nitrobenzene phase and aqueous phase initially containing no surfactant. 

FIG. 6 Electrical potential oscillation across the octanol membrane with sodium dodecyl sulfate as surfactant (A) and between octanol and aqueous phases (B and C). All data were obtained using the inverted U-shaped cell (al) water, (a2) 8mM sodium dodecyl sulfate and 5M ethanol, (b) octanol containing 8mM tetrabutylammonium chloride, (c) Ag/AgCl electrode, (d) KCl salt bridge, and (e) saturated KCl. (Ref. 26.)... 

Figure 3.1 shows the appearance of dihydromethysticin in the acceptor well as a function of time [15], The solid curve is a least-squares fit of the data points to Eq. (1), with the parameters Pe = 32 x 10-6 cm s 1, R = 0.42, and t s = 35 min. The membrane retention, R, is often stated as a mole percentage (%R) of the sample (rather than a fraction). Its value can at times be very high - up to 90% for chlor-promazine and 70% for phenazopyridine, when 2% wt/vol DOPC in dodecane is used. Figure 3.2 shows a plot of log %R versus log Ka(7.4), the octanol/water apparent partition coefficient. It appears that retention is due to the lipophilicity of molecules this may be a good predictor of the pharmacokinetic volume of distribution or of protein binding. 

In addition, the steric bulk of several substituents on an amino group appears to disturb the structure of the membrane more than a single substituent. Amw for a series of (/>-mcthylbcnzyl)alkylamincs increase with increasing alkyl chain length [153]. This trend was not observed for the corresponding octanol-water partition data, which is additional evidence that the increase in Amw is caused by an unfavourable steric constraint. The positively charged... 

Litman etal. [ 391 analyzed a set of 34 diverse drugs and their effect on the kinetics of the ATPase activity of the microsomal membrane fraction of a P-gp overexpressing CHO cell line. They found a correlation (r=0.75) between the affinity of the modulators and their van der Waals surface area, while the affinity data did not correlate with the lipophilicity of the compounds, expressed as calculated octanol/ water partition coefficients. 

Note Data represent the mean S.E. (n = 3). MW, molecular weight P0/w, octanol-to-water partition coefficient CLapp, apparent membrane permeability clearance SI, midgut area of the small intestine NA, not available or applicable. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and L-camitine and 30 min for the others. For those that are transported by carriers in part (riboflavin and glycerol in both colon and SI, and L-carnitine, 5-fluorouracil, and cephradine in SI), absorption was evaluated at higher concentrations where the contribution of carrier-mediated transport is negligible. Values of P0/w were obtained from a report by Leo et al. [30] except for that of D-xylose, which was determined in our laboratory. a Data by single-pass perfusion experiments. b Unpublished data from our laboratory. 

Despite the limitation of octanol as a solvent for predicting membrane partitioning, because of the enormous body of data that already exists and the ease of generating data, it undoubtedly remains the partitioning solvent of choice. Recent advances in the methodology for determining liposomal membrane-water partition coeifients should make the liposome a more popular membrane system for partition coef cient determination in the future. 

Nevertheless, log Poet. will remain an important tool because it has provided excellent service during the last three decades in QSAR studies, and large data bases are available. But we should remember also that membranes are not made of octanol and membranes are not uniformly made of one type of phospholipid. 

The importance of hydrogen bonds for dmg-membrane interaction and transport has been stressed recently [20]. The authors analyzed the data of Vaes et al. [21] regarding the partitioning of polar and non-polar chemicals into SUVs of L-a-dimyris-toylphosphatidylcholine and into octanol. Descriptors used were a bulk descriptor, a, and the H-bond acceptor and donor strength, LC EQ. Regression analysis led to Eq. 4.8 ... 

Both descriptors alone led to correlations with lower statistical significance. The data set included basic, acidic, and neutral drugs (Table 4.23). According to the authors, the difference log Doct - log k IAM describes the equilibrium of the drug between n-octanol and phospholipid membrane phase. ... 

These aspects of MDR as well as the presented data underline the statement that permeability properties of compounds - especially their amphiphilic nature - cannot sufficiently be described through their partition coefficient in the octanol-buffer system because of special interactions with the phospholipids constituting the membrane. 

Finely Porous Model. In this model, solute and solvent permeate the membrane via pores which connect the high pressure and low pressure faces of the membrane. The finely porous model, which combines a viscous flow model eind a friction model (7, ), has been developed in detail and applied to RO data by Jonsson (9-12). The most recent work of Jonsson (12) treated several organic solutes including phenol and octanol, both of which exhibit solute preferential sorption. In his paper, Jonsson compared several models including that developed by Spiegler eind Kedem (13) (which is essentially an irreversible thermodynamics treatment), the finely porous model, the solution-diffusion Imperfection model (14), and a model developed by Pusch (15). Jonsson illustrated that the finely porous model is similar in form to the Spiegler-Kedem relationship. Both models fit the data equally well, although not with total accuracy. The Pusch model has a similar form and proves to be less accurate, while the solution-diffusion imperfection model is even less accurate. 

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