1 In order to obtain an understanding of the risks associated with dermal uptake of xenobiotics it is necessary to investigate the principles governing percutaneous absorption and metabolism. The sin gle-pass perfused rabbit ear served as a convenient model for the simultaneous study of absorption and metabolism of a variety of substances.
We found:
2 When substances are applied in a lipophilic vehicle the permeation coefficient K P is notably decreased when the distribution coefficient (n-octanol/perfusion buffer (pH 7.4)) Poct. exceeds 2000. KP also decreases with increasing molecular weight.
3 Substances which are in the ionized state at pH 7.4 may have a higher permeation coefficient than would be expected from Poct. or by molecular weight.
4 The partition of a drug from the stratum corneum to the epidermal enzymes controls the extent of its metabo lism. However, substances with increased solubility at physiological pH are metabolized to a lesser extent than expected from their absorption rate.
Scheuplein RJ, Bronaugh RLPercutaneous absorption. In: Biochemistry and physiology of the skin. Goldsmith LA (ed.) Oxford University Press , Oxford, 1983; pp 1255-1295.
2.
Baron J. et al. Identification of intratissue sites for xenobiotic activation and detoxication. In: Biological reactive intermediates III . Kocsis JJ, Jollow DJ, Witmer ChM, Nelson JO, Snyder R (eds.) Plenum Press, New York and London, 1986; pp 119-144.
3.
Pendlington RU et al. Distribution of xenobiotic metabolizing enzymes in skin. Toxicol in Vitro1994; 8: 525-527.
4.
Kappus H.Drug metabolism in the skin. In: Pharmacology of the skin II . Greaves MW, Shuster S (eds.) Springer Verlag, Berlin, 1989; pp 123-163.
5.
Kao J., Carver MPCutaneous metabolism of xenobiotics. Drug Metab Rev1990; 22: 363-410.
6.
Behrendt H., Kampffmeyer HGAbsorption and ester cleavage of methyl salicylate by skin of single-pass perfused rabbit ears. Xenobiotica1989; 19: 131-141.
7.
Henrikus BM, Breuer W., Kampffmeyer HGDermal metabolism of 4-nitrophenol and 4-nitroanisole in single-pass perfused rabbit ears. Xenobiotica1991; 21: 1229-1241.
8.
Henrikus BM, Kampffmeyer HGEster hydrolysis and conjugation reactions in intact skin and skin homogenate, and by liver esterase of rabbits. Xenobiotica1992; 22: 1357-1366.
9.
Henrikus BM, Kampffmeyer HGMetabolism of ethyl 4-aminobenzoate in the isolated single-pass perfused rabbit ear. SkinPharmacol1993; 6: 246-252.
10.
Bast GE, Kampffmeyer HGAbsorption and metabolism of hydrocortisone 21-butyrate, 21-hemisuccinate and hydrocortisone by skin of the rabbit ear during single-pass perfusion . Xenobiotica1994; 24: 1029-1042.
11.
Bast GE, Kampffmeyer HGNo effect of albumin on the dermal absorption rate of hydrocortisone 21-butyrate, permethrin or diflunisal in the isolated, single-pass perfused rabbit ear . Skin Pharmacol1996; 9: 327-333.
12.
Bast GE, Taeschner D., Kampffmeyer HGPermethrin absorption not detected in single-pass perfused rabbit ear, and absorption with oxidation of 3-phenoxybenzyl alcohol. Arch Toxicol1997; 71: 179-186.
13.
Albery WJ, Hadgraft J.Percutaneous absorption: in vivo experiments. J Pharm Pharmacol1979; 31: 140-147.
14.
Kampffmeyer HGAbsorption and metabolism of xenobiotics by skin of rabbit ears. Metabolic Aspects of Cell Toxicity. Eyer P (ed.) BI-Wissenschaftsverlag, Mannheim, 1994; pp 81-93.
15.
El Tayar N. et al. Percutaneous penetration of drugs: a quantitative structure-permeability relationship study. J Pharm Sci1991; 80: 744-749.
16.
Scott RC et al. In-vitro percutaneous model for quantitative structure-absorption studies. J Pharm Pharmacol1986; 38: 66P.
Storm JE et al. Metabolism of xenobiotics during percutaneous penetration: role of absorption rate and cutaneous enzyme activity. Fund Appl Toxicol1990; 15: 132-141.
19.
Wang L. et al. Determination of the n-octanol/water partition coefficients of polycyclic aromatic hydrocarbons and estimation of aqueous solubilities . Acta Sci Circumstantiae1986; 6: 491-497.
20.
Higuchi T., Davis S.Thermodynamic analysis of structure-activity relationships of drugs: prediction of optimal structure. J Pharm Sci1970; 59: 1376-1383.
