Comparative in vitro-in vivo percutaneous penetration of the fungicide ortho-phenylphenol.
The validity of in vitro and in vivo methods for the prediction of percutaneous penetration in humans was assessed using the fungicide ortho-phenylphenol (OPP) (log Po/w 3.28, MW 170.8, solubility in water 0.7 g/L). In vivo studies were performed in rats and human volunteers, applying the test compound to the dorsal skin and the volar aspect of the forearm, respectively. In vitro studies were performed using static diffusion cells with viable full-thickness skin membranes (rat and human), nonviable epidermal membranes (rat and human), and a perfused pig ear model. For the purpose of conducting in vitro/in vivo comparisons, standardized experimental conditions were used with respect to dose (120 microg OPP/cm(2)), vehicle (60% aqueous ethanol), and exposure duration (4 h). In human volunteers, the potentially absorbed dose (amount applied minus dislodged) was 105 microg/cm(2), while approximately 27% of the applied dose was excreted with urine within 48 h. In rats these values were 67 microg/cm(2) and 40%, respectively. In vitro methods accurately predicted human in vivo percutaneous absorption of OPP on the basis of the potential absorbed dose. With respect to the other parameters studied (amount systemically available, maximal flux), considerable differences were observed between the various in vitro models. In viable full-thickness skin membranes, the amount systemically available and the potentially absorbed dose correlated reasonably well with the human in vivo situation. In contrast the K(p)/maximal flux considerably underestimated the human in vivo situation. Although epidermal membranes overestimated human in vivo data, the species differences observed in vivo were reflected correctly in this model. The data generated in the perfused pig ear model were generally intermediate between viable skin membranes and epidermal membranes.
Cnubben
Nicole H P
NH
Department of Explanatory Toxicology, TNO Nutrition and Food Research, Utrechtseweg 48, 3700 AJ Zeist, The Netherlands.
Elliott
Graham R
GR
Hakkert
Betty C
BC
Meuling
Wim J A
WJ
van de Sandt
Johannes J M
JJ
D000279:Administration, Cutaneous; D000328:Adult; D000818:Animals; D021461:Animals, Outbred Strains; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption; D013552:Swine
D001713:Biphenyl Compounds; D005659:Fungicides, Industrial; C004369:2-phenylphenol