Influence of solubility and permeant size on absorption and metabolism of xenobiotics in rabbit skin

Abstract

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 single-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 Kr is notably decreased when the distribution coefficient (n-octanol/perfusion buffer (pH 7.4)) Poct. exceeds 2000, Kr 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 metabolism. However, substances with increased solubility at physiological pH are metabolized to a lesser extent than expected from their absorption rate. 5 The decrease in percutaneous absorption and metabolism of a substance with a Poct. exceeding 2000 is consistent with the assumption that high lipophilicity hinders partition of the substance from the stratum corneum to the viable metabolizing tissue.