Extent of cutaneous metabolism during percutaneous absorption of xenobiotics.
In vitro percutaneous absorption studies generally do not determine whether biotransformation occurs during passage of a substance through the skin. Since it has recently been demonstrated that several chemicals are metabolized during skin permeation, we investigated the metabolism of five additional compounds (14C-labeled) after application to fuzzy rat skin: caffeine, p,p'-DDT, butylated hydroxytoluene (BHT), salicylic acid, and acetyl ethyl tetramethyltetralin (AETT). The viability of skin was maintained with a tissue culture medium. Radioactivity of each substrate and any metabolites in skin and receptor fluid was measured so that the absorption and metabolism of water-insoluble compounds would be accurately determined. Percutaneous absorption ranged from a low of 13% of the applied dose for BHT to a high of 49% for DDT. BHT was metabolized in skin to 4-hydroxy-BHT and an unknown metabolite. Of the absorbed radioisotope, 6.6% was isolated in biotransformed products found mainly in the receptor fluid. AETT was also metabolized during absorption, with 1.9% of the absorbed radioisotope found in two unknown peaks. Caffeine, DDT, and salicylic acid were not metabolized during skin permeation. Skin and liver microsomal metabolism was measured for all compounds except DDT. Metabolism in skin was observed only for the compounds also biotransformed in the diffusion cell; BHT and AETT were metabolized at 113 and 2.5 pmol/min/mg protein, respectively. In this study, as in others, skin metabolism was substantially less than the corresponding metabolism in liver. Therefore, a low rate of liver metabolism such as that found for caffeine, salicylic acid, and DDT might often be predictive of the absence of measurable metabolism during skin permeation. It seems likely that for many compounds, the biotransformations in skin will be small in terms of the percentage of absorbed material that is metabolized. Nevertheless, with potent compounds, even small quantities of a metabolite can be important and for pharmacokinetic studies, viability of skin must be maintained.
Bronaugh
R L
RL
Division of Toxicological Studies, Food and Drug Administration, Washington, D.C. 20204.
Stewart
R F
RF
Storm
J E
JE
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000493:pharmacokinetics; D002110:Caffeine / Q000493:pharmacokinetics; D003634:DDT / Q000493:pharmacokinetics; D005260:Female; D010477:Perfusion; D051381:Rats; D012459:Salicylates / Q000493:pharmacokinetics; D020156:Salicylic Acid; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics; D015262:Xenobiotics / Q000378:metabolism*
D012459:Salicylates; D013764:Tetrahydronaphthalenes; D015262:Xenobiotics; D002084:Butylated Hydroxytoluene; D002110:Caffeine; C023054:versalide; D003634:DDT; D020156:Salicylic Acid