Permeability coefficients in hairless

Butanol, permeability coefficients in hairless mouse skin, 246,247/... 

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

Figure 15.7 shows the permeability coefficient regression equations for skin from human (EquationT15.1-l), hairless mouse (EquationT15.1-2), hairless rat (Equation T15.1-3), rat (Equation T15.1-6), and shed snake (Equation T15.1-7) plotted as a function of log for relatively small molecules MW = 100) and larger molecules MW = 300). The regression equations for human, hairless mouse, and shed snake skin are most relevant because these databases are the largest and most diverse. Permeability coefficients in all species increase linearly with log... 

As illnstrated in Fignre 15.7, differences between species in the dependence of permeability coefficients can cause the relative order of penetration rates to change with For example, for a chemical with MW = 100 and log = 4, the predicted order for the permeability coefficients is snake > hairless mouse > human for a chemical with MW = 100 and log = -2.0, the predicted order is hairless mouse > human > snake. However, when MW = 300, the relative order among these three species is predicted to be independent of log These plots show clearly that relative rankings of permeability coefficients in different species may depend on chemical properties of the penetrant. 

Behl et al. studied the effect of prolonged contact of hairless mouse skin with water on permeability coefficients. The authors showed that permeability coefficients increase after extended periods of hydration. Because other permeability coefficients in the database we have assembled were measured on previously unhydrated skins or skins that were hydrated for short periods, the permeability coefficients with the shortest hydration time (0.3 to 0.8 h) from Table 1 were selected for the validated database. Permeability coefficients were determined with either water or ethanol as a copenetrant. The concentrations were dilute (alcohol concentrations less than 10 M) and probably were not damaging. Six reported measurements were averaged for methanol, two for ethanol, and two for butanol, and permeability coefficients were reported singly for hexanol, heptanol, and octanol. Although this article did not specify the diffusion cell temperature, subsequent articles by the same authors describing similar data indicated that the temperature was 37°C (e.g., Behl and Barrett, 1981 Behl, El-Sayed, et al., 1983 Behl, Linn, et al., 1983). It seems hkely that the temperature was also 37°C in the experiments described in this article. 

Permeability coefficients in this article are different from permeabihty coefficients in another related article (Hatanaka et al., 1990) because different hairless rat strains were used. The permeabihty coefficients for diclofenac sodium, dopamine hydrochloride, isoproterenol hydrochloride, indomethadn, and water were reported in the... 

The purpose of this report is to present results on (a) the effect of ethanol on the transport of 8-estradiol across hairless mouse skin and (b) the effect upon the effective permeability coefficient as solvent compositions are independently varied in the donor and receiver chambers. Also, since there is evidence for pore formation, at least at the highest ethanol levels, a novel pore model... 

A new theoretical model will now be described aimed at attempting to provide a possible explanation for the deviations observed in Figure 3. The model assumes that significant porosity prevails in the hairless mouse stratum corneum when ethanol is present. Although it can be assumed, that at low ethanol concentrations (below 50%) ethanol fluidizes lipid bilayers, there is evidence, that ethanol at high concentration (over 50%) may induce significant pore formations in hairless mouse stratum corneum as measured by the substantial increase of tetraethylammonium bromide permeabilities (10). The permeability coefficient P of a solute across a membrane or stratum corneum under steady state conditions may be described by ... 

Figure 9 (A) lontophoretic flux of various cations across excised pig skin versus molecular weight. The donor concentration was 1.0 M of drug as chloride salt. (Data from Ref. 108.) Key. ( ) monovalent ions, (O) divalent ions. (B) Normalized cathodal iontophoretic flux of anionic solutes across hairless mice versus molecular weight. (Data from Ref. 109.) (C) Cathodal iontophoretic permeability coefficient of alkanoic acid across nude rat skin versus molecular weight. (From Ref. 64.) (D) Comparison of transport number and molecular weight in human epidermis.

Figure 15.1 through Figure 15.6 show skin permeability coefficient measurements from hairless mouse, hairless rat, rat, shed snake, and the lesser-studied animals (guinea pig, marmoset, rabbit, pig, dog, mouse, nude rat) plotted as a function of log In Figure 15.1 to Figure 15.4 and Figure 15.6, compounds that were more than 90% ionized are identified by the form of the dominant ionic species (that is, cation, anion, or zwitterion) and labeled as excluded. Ionized species with undetermined log are plotted to the left of the dashed vertical line located at log = -6.0. Cations are plotted at log = -6.5, anions at log = -7.0, and zwitterions at log = -7.5. A few permeability coefficient measurements that are... 

Table A1 lists and Figure 15.1 shows 144 permeability coefficient values for 83 eompounds (83 fully validated and 61 excluded data points 45 fully validated compounds) measured in hairless mouse skin. All of the measurements excluded from this database were more than 90% ionized. Etorphine is distinguished on this figure because Vecchia and Bunge (2002b) used the fact that the human permeability coefficient is larger than the hairless mouse permeability coefficient to support exclusion of the measurement from the fully validated database for human skin. Notice that the hairless mouse permeability coefficient of etorphine is consistent with measurements for other cations, which was not the case with the human permeability coefficient for etorphine (Vecchia and Bimge, 2002b).

There are fewer extremely low (i.e., logP < -4.0) permeability coefficient values in hairless mouse skin than in human skin. 

Table A2 tabulates and Figure 15.2 shows 41 permeability coefficient values of 33 different compounds (18 fully validated and 23 excluded data points 14 fully validated compounds) measured in hairless rat skin. The database contains permeability coefficients for structurally diverse compounds, predominantly pharmaceutically active compounds, with varied chemical properties. Vinpocetine was excluded because (1) the concentration was not reported, and as a result the fraction unionized could not be determined and (2) could not be reliably calculated (vinpocetine has structural fragments that are not adequately represented in Daylight software PCModels, 1995). Vinpocetine is plotted at the calcidated value for log...

Table A3 tabulates and Figure 15.3 shows 17 permeability coefficient values for 11 compoimds (14 fully validated and 3 excluded data points 10 fully validated compoimds) measured in rat skin. This database is small and consists mainly of phenols, alcohols, and water. Because all chemicals in this database are of relatively low MW and many are structurally related (meaning that MW and log are correlated), log is more clearly linear with log than in Figure 15.1 and Figure 15.2. Water permeability coefficients are similar to human skin (i.e., 1.47 x 10" cm h" in rats compared to 1.18 x 10" cm h in humans). However, the permeability coefficient for paraquat in the rat is significantly higher than in humans (i.e., 3.07 X 10" cm h in rats compared to 8.70 x lO- cm h" in humans, a ratio of about 35). Paraquat permeability was similar in the haired and hairless rat.

Dermal absorption in different animal species has many qualitative similarities to dermal absorption in humans that can be observed through examination of permeability coefficients. However, for the purpose of estimating dermal absorption in humans, the large numbers of permeability coefficient values determined in animal skins are of limited use until quantitative relationships to human skin are established. Based on the data collected so far, we have developed regression equations of permeability coefficients as functions of log and MW for several animal species (hairless mouse, hairless rat, rat, and snake). The regression equation from hairless mouse skin is similar to an equation of the same form for human skin. On average, hairless mouse skin is 3.1 times more permeable than human skin this ratio appears to be independent of but may increase weakly for higher MW compounds. 

Based on the analysis of the small data sets examined hme, the permeability coefficient ratio may not be constant for other species of animals. In particular, there is some evidence that the ratio may depend on MW or for some species. For example, for the shed snake skin data examined here, Ihe pmmeahility coefficient in snake was affected more by MW and log than human skin thus, the permeability coefficient ratio for snake and human skins appears to vary with MW and log K. Based on our present data sets, the ratio of permeabiUty coefficients for hairiess rat and rat skin compared with human skin also may depend on log and MW. However, the data sets for these animal species are so small that this conclusion cannot be supported with confidence. Until more data are compiled to better define these relationships, we recommend using the average ratios of 2.3 for hairless rat skin and 1.9 for rat skin. 

Permeability coefficients for hydrocortisone and 21-n-alkyl ethers of hydrocortisone were taken without alteration from Table 1. According to this article, these measurements were made on the SKH-hr-1 hairless mouse (although the authors referred to this strain as a nude mouse). As in Ackermann and Hynn (1987), the temperature was not specified. Nevertheless, it seems likely that the temperature was 37°C (Ackermann, 1983 Ackermann et al., 1985 Durrheim et al., 1980). 

The permeability coefficient of rficorandil in hairless mouse given in Table 1 was not reported previously (Sato et al., 1989). 

Stereoselectivity in the metabolism and percutaneous permeation, related to skin enzymatic activity, was reported for several compounds [23-28]. Stereoselectivity in permeation and cutaneous hydrolysis of several ester prodrugs of propranolol through hairless mouse skin was investigated [23]. The authors reported the stereoselective hydrolysis of propranolol prodrugs that is notably biased towards the R-isomer, which resulted in the enantioselective permeation. The lipophilicity of prodrugs, expressed as the partition coefficients, was found to affect the apparent skin permeability coefficients. The more lipophilic prodrugs readily entered into the stratum corneum, but their clearance into hydrophilic deeper strata (epidermis and dermis), where drug hydrolysis takes place, was much less effective. Unlike S-isomers, the R-isomers of propranolol esters were entirely hydrolyzed in epidermis and freely crossed the dermis strata. 

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