Comparison with the Flynn Permeability Coefficient Database

The FV database contains 170 permeability coefficient values for 127 compounds, encompassing many different organic compound structural classes. The entire FV database is broad in the sense of log Kow (-3.10 [mannitol] < log Kow < 4.57 [decanol]; mean = 1.66, median = 1.94, standard deviation = 1.75) andMW (18.0 [water] < MW 584.6 [ouabain]; mean = 201.9, median = 160.25, standard deviation = 129.11) and should be useful for predicting permeability coefficient values for a diverse set of organic compounds. Permeability coefficients for large MW compounds (MW > 600) are not represented in the database and cannot be accurately estimated. The FV database has measurements for only 13 hydrophilic compounds (defined as log Kow < 0.0): 2,3-butanediol, caffeine, ethanol, 2-ethoxy ethanol, a-hydroxyphenyl acetamide, mannitol, methanol, N-nitrosodiethanolamine, ouabain, p-phenylenediamine, scopolamine, urea, and water.

By contrast, Flynn (21) assembled 97 human skin permeability coefficient values for 94 compounds with a relatively broad range of log Kow (- 2.25 [sucrose] < log K0w < 5.49 [HC-21-yl octanoate]; mean = 2.05, median = 2.03, standard deviation = 1.40) and MW (18 [water] < MW < 765 [digitoxin]; mean = 238.4, median = 184.2, standard deviation = 148.8). These statistics are based on the values of log Kow reported by Flynn (21) for all but four compounds (chlorpheniramine, diethylcarbamazine, N-nitrosodiethanolamine, and ouabain). Values of Kow for these compounds were either obtained from Hansch et al. (1) (chlorpheniramine and ouabain) or calculated using Daylight software (2) (diethylcarbamazine and N-nitrosodiethanolamine). The Flynn database includes three in vivo measurements (for benzene, styrene, and toluene). There are nine hydro-philic (log Kow < 0.0) compounds in the Flynn database (2,3-butanediol, ethanol, 2-ethoxy ethanol, methanol, N-nitrosodiethanolamine, ouabain, sucrose, scopolamine, and water). Only four (N-nitrosodiethanolamine, ouabain, sucrose, and water) of those compounds have a log Kow < -1.

Names of compounds listed in the FV database (Table A1) with permeability coefficient values in the Flynn database are contained within brackets. Updated values (2) have replaced the «-alcohol permeability coefficients appearing in the Flynn database (34). (The only practical difference is that a lower permeability coefficient for propanol [1.2 X 10-3 cm h-1] replaced the value [1.4 X 10-3 cm h-1] included in the Flynn database.) In vivo measurements included in the Flynn database [ethylbenzene, styrene, and toluene from (35,36)] were excluded from the current analysis. The measured permeability coefficient of hydrocortisone (37), determined from a 5% ethanol vehicle, and the permeability of naproxen, determined from an aqueous gel vehicle, were placed in the excluded database. Likewise, etorphine was excluded since Jolicoeur and others (33) identified it as being very different from quite similar compounds, and much different in hairless mouse skin. Digitoxin was excluded since the measurement was probably not at steady state. Subsequent investigations for morphine (38) and fentanyl and sufentanil (4) were considered in addition to the prior investigation (5) cited in the Flynn database. Various compounds from the Flynn database were excluded because more than 90% of the compound was ionized in the experiments.

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