Octanol, permeability coefficients

The summary of Pe values for the steroids as a function of stirring rates is found in Table 11 and their correlations with log PC (n-octanol-water) in Figure 20. The transport kinetics of the relatively hydrophilic hydrocortisone and dexa-methasone are controlled by passive diffusion across the cell monolayer. On the other hand, the Pe values of testosterone and progesterone are highly dependent on stirring rate. The results for testosterone are used to obtain the relationships between the effective permeability coefficients of the ABL on the donor and receiver sides and the stirring rate, using the linear expression (see Eq. (69)]... 

Figure 22 Correlation between the log permeability coefficient for a series of peptides across a Caco-2 cell monolayer in the Transwell system and A log PC, which is defined as log PC(n-octanol/water) — log PC (isooctane/water). [Redrawn from Burton et al. (1992) with permission from the publisher.]...

Figure 26 Correlation of the effective permeability coefficients of (3-blockers determined at pH 6.5 (O) and 7.4 ( ) with stirring rates and log partition coefficients (n-octanol/buffer at pH 6.5 and 7.4). APL, alprenolol ATL, atenolol PDL, pindolol PPL, propranolol.

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Based on the 96-well format, OCT-PAMPA was proposed and has proved its ability to determine (indirectly) log Poet [87]. PAM PA is a method, first developed for permeability measurements, where a filter supports an artificial membrane (an organic solvent or phospholipids) [88, 89]. With this method, the apparent permeability coefficient (log P ) of the neutral form of tested compounds is derived from the measurement of the diffusion between two aqueous phases separated by 1-octanol layer (immobilized on a filter). A bilinear correlation was found between log Pa and log Poct> therefore log Poet of unknown compounds can be determined from log Pa using a calibration curve. Depending on the detection method used a range oflog P within —2 to +5 (with UV detection) and within —2 to +8 (with LC-MS detection) was successfully explored. This method requires low compound amounts (300 pi of 0.04 mM test compound) and, as for the previous method, samples can be prepared in DM SO stock solutions. For these experiments, an incubation time of 4h was determined as the best compromise in term of discrimination. The limitation of the technique lies in the lower accuracy values... 

Permeability Studies. The permeability coefficients for the four solutes plotted as a function of temperature are shown in Figure 1. Hydrocortisone experiences an increase in permeability coefficients of 10 between 10 and 70°C, while butanol and octanol experience increases in permeability coefficients of 102 over the same temperature range. The permeability coefficient of ARA-A increases by a factor of 10 between 40 and 70°C. 

Figure 1. Permeability coefficients in full-thickness hairless mouse for hydrocortisone, butanol, octanol and ARA-A as a function of temperature.

To help establish the relevance of a skin sensitization alert from DEREK for Windows, the system incorporates reasoning that allows the determination of skin permeability coefficients (log Kp values) according to the algorithm developed by Potts and Guy (1990). DEREK for Windows derives log Kp from the logarithm of the octanol/water partition coefficient (log Kow) using the following equation (Moriguchi et al., 1992) ... 

Potts and Guy [2] examined a large dataset of permeability coefficients ( 90) and have determined a simple relationship between A p and two fundamental physicochemical constants—the octanol water partition coefficient (Koct) and the molecular weight of the permeant (MW). 

Fig. 8 Cyclic variation in the apparent permeability coefficient, Tapp of methanol and n-octanol in the female rhesus monkey in response to its estrus cycle. The bars indicate the time of observed menstruation. (From Ref. l)...

Most structure-permeation evaluations of transdermal transport indicate the strong relationship between a chemical s permeability coefficient across the skin (Aip) and its lipophilicity. Potts and Guy analyzed a diverse database of skin penetration data, comprising 91 compounds and developed a simple relation indicating that Kp depended only on lipophilicity, as measured by the chemical s octanol-water partition coefficient (P), and molecular weight (MW) ... 

Table 27.3 Permeability Coefficients (A ) in Human Breast Skin and Octanol Water Partition Coefficients for THMs in Water[nl...

Predicted octanol/water partitioning coefficient Fraction of the oral dose absorbed Apparent permeability coefficient... 

Figure 15.33. In vivo log permeability coefficient of rat brain capillaries (log Rnn) as a function of log octanol/water partition coefficient (logPo/ ), the most commonly used measure of lipophilicity. For compounds in italic, the log distribution coefficient measured at physiological pH was used (logDp/ ). Values denoted with a star are for guinea pig. The strong deviants below the line that are denoted with diamonds are known substrates for P-glycoprotein, a multidrug transporter that actively removes them from the brain.

Drug penetration into the eye is approximately linearly related to its concentration in the tear film. Certain disease states, such as comeal ulcers and other comeal epithelial defects, may increase drug penetration when anatomic barriers are compromised or removed. Experimentally, drugs may be screened for their potential clinical utility by assessing their comeal permeability coefficients. These pharmacokinetic data combined with the drug s octanol/water partition coefficient (for lipophilic drugs) or distribution coefficient (for ionizable drugs) yield a parabolic... 

It is possible to modulate the likelihood levels by relationships with experimental or calculated physicochemical (or other) parameters such as octanol-water partition coefficients. Such calculators may be external to the main program. For example, within the skin sensitisation endpoint, a very low skin permeability coefficient (Log Kp),as calculated from the molecular weight and the octanol-water partition coefficient estimation using the method of Potts and Guy, reduces the default skin sensitisation alert likelihood from plausible to equivocal (Figure 11.4). 

Fig. 5. Calculated relative intramembrane diffusion coefficients across the human red blood cell membrane as a function of molecular weight. Abscissa molecular weight on a hnear scale. Ordinate permeability coefficients from Fig. 4 divided by relevant octanol/water partition coefficients (listed in (41).

To test whether the barrier for steroids was the same as the barrier for the smaller solutes, Giorgi also measured the permeabilities and partition coefficients for some smaller molecules. Some of these data are reproduced in Fig. 10 as a log/log plot of permeabihty coefficients against n-octanol partition coefficients. Clearly the data for the small solutes and for the steroids fall on a fairly good straight line, suggesting that the same rate law holds for the permeation of the steroids as for that of the smaller solutes. All seem to encounter a rate-limiting permeability barrier which has... 

Fig. 10. Calculated intramembrane diffusion coefficients across membranes of (A) Nil 8 hamster fibroblasts and (B) the HTC rat hepatoma cell line, as a function of molecular weight of the permeant. Ordinate logarithm of membrane thickness, taken as 50-10 cm, multiplied by the permeability coefficient (in cm/sec) and divided by the octanol/water partition coefficient. Abscissa logarithm of molecular weight. Data taken from Giorgi and Stein [19]. Permeants indicated as follows large circle, mean value for all the steroids of Fig. 8 Ur, urea Thw, thiourea Gly, glycerol Ap, antipyrine. Regression lines through the points have slopes of —3.9 for the Nil 8 cells and —3.7 for the HTC cells.

Note Permeability coefficients Kp, octanol-water partition coefficients P, and molecular weight (MW) for 94 compounds listed by Flynn (1990). 

In terms of the descriptors used in the prediction of skin permeability coefficients, the octanol-water partition coefficient F is a well-established measure of hydro-phobicity (Dearden, 1990). There is a variety of algorithms to calculate log P, including Web-based programs and the KOWWIN software, which is part of the EPISuite utility. EPISuite is available free from the U.S. Environmental Protection Agency (see Cronin and Livingstone, 2004b, for more details EPISuite can be downloaded from http //www.epa.gov/oppt/exposure/docs/episuite.htm). Molecular size is well modeled by molecular weight, which of course is fimdamental and trivial to calculate. 

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