Percutaneous absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate: comparison of in vitro and in vivo results in the hairless guinea pig.
The in vitro and in vivo absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate (DEHP) were investigated in the hairless guinea pig. The in vitro method, which involved the use of flow-through diffusion cells and Hepes-buffered Hanks' balanced salt solution containing 4% bovine serum albumin as perfusate, was demonstrated to be a suitable system for predicting in vivo absorption of the above lipophilic compounds. The successful application of the in vitro technique for these compounds is significant because no satisfactory in vitro method has hitherto been developed to predict in vivo absorption of highly lipophilic chemicals. Quantification of parent compounds and metabolites that permeated into perfusates and those that remained in skin discs provided insight into the process by which the chemicals penetrated through the skin. Pyrene was absorbed primarily by a passive diffusion process, although a small fraction of the administered dose was biotransformed into metabolites in the skin and partitioned into the receptor fluid. Absorption of benzo[a]pyrene was mediated by biotransformation processes. A metabolite derived from the ultimate carcinogen of this compound, benzo[a]pyrene r-7, t-8,9,10-tetrahydrotetrol, was identified in the receptor fluid. Most of the administered DEHP remained in the skin and only a very small fraction of the dose partitioned into the receptor fluid in either viable or nonviable skin. Data from the present study led to the conclusion that the in vitro method can be utilized to predict in vivo absorption for compounds of high lipophilicity and that dermal metabolism facilitates partitioning of metabolites into the receptor fluid and hence may affect the biological activities of dermally applied compounds.
Ng
K M
KM
Environmental and Occupational Toxicology Division, Environmental Health Directorate, Ottawa, Ontario, Canada.
Chu
I
I
Bronaugh
R L
RL
Franklin
C A
CA
Somers
D A
DA
D000279:Administration, Cutaneous; D000818:Animals; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D011721:Pyrenes / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D012869:Skin Absorption / Q000187:drug effects*; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D011721:Pyrenes; D001564:Benzo(a)pyrene; D010664:Phenylmethylsulfonyl Fluoride; C030984:pyrene; D004051:Diethylhexyl Phthalate