Hairless mouse skin permeability coefficients

Table A1 Hairless Mouse Skin Permeability Coefficient Measurements... 

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... 

Differential scanning calorimetric and infrared spectroscopic investigations of intact stratum corneum, extracted lipids and keratinized protein residue sheets suggested the thermal transitions occurring within the 30 to 70°C region were associated with increased molecular mobility of the lipids. The permeability coefficients of lipophilic molecules through hairless mouse skin increased by several orders of magnitude over the same temperature... 

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

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. 

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. 

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. 

The permeability coefficient of etorphine was taken from Table I. Three measurements on hairless mouse skin were averaged. 

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. 

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... 

Figure 15.7 Permeability coefficient regressions for human, hairless mouse (HLMouse), hairless rat (HLRat), rat, and shed snake skin plotted as a function of log K at (a) MW = 100 and (b) MW = 300 human (solid), satisfactory correlation (long dashes), limited correlation (short dashes).

Permeability coefficients were taken without alteration from Table 2 for fuU-thick-ness skin of the SKH-hr-1 hairless mouse (although the authors referred to this strain as a nude mouse). This article does not specify temperature, although other citations by the same authors indicated that the temperature was 37°C (Ackermann, 1983 Ackermann etal., 1985). 

Table 6 Cumulative Penetrated Amount at 10 h (Qio), Steady State Flux (/s) Permeability Coefficient ( p), Lag Time (t), and Hydrolyzed Percentage (after 10 h) of the Isomers of Propranolol Prodrugs Through Full-Thickness Skin of Hairless Mouse... 

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