title: In vitro evaluation of the permeation of cytotoxic drugs through reconstructed human epidermis and oral epithelium.
abstract: BACKGROUND
  Occupational exposure to antineoplastic agents may represent a risk to health care workers, although the relevance of different exposure routes is not fully understood. The objectives of this study were to determine in vitro permeation of four widely used cytotoxic drugs (cisplatin, cyclophosphamide, doxorubicin, and fluorouracil) through two reconstituted tissue models representing human skin epidermis and oral mucosa.
  
  
  METHODS
  Experiments were conducted with reconstructed models of human epidermis and oral epithelium, cultured in a chemically-defined medium under conditions simulating possible exposure scenarios (6 h duration, three concentrations corresponding to commonly used application doses). The amounts of drugs permeated through the tissues into the receptor media were determined using ultra performance liquid chromatography with photospectrometric detection.
  
  
  RESULTS
  The highest epidermis permeations (P = 0.2 x 10(-3) - 1.5 x 10(-3) cm x h(-1)) were observed with three polar drugs (cisplatin, cyclophosphamide and fluorouracil), while permeation by more hydrophobic doxorubicin was minor (P(max) = 0.03 x 10(-3) cm x h(-1)). As expected, more pronounced tissue permeation was observed with the reconstructed oral epithelium having the maximum permeability coefficient (P = 180 x 10(-3) cm x h(-1)) for cisplatin and fluorouracil. Histological evaluation of the exposed tissues revealed cytotoxic effects at higher doses, especially for oral epithelium.
  
  
  CONCLUSIONS
  Although the skin epidermis with keratinised stratum corneum provided relatively good protection, uptake (of at least some investigated drugs) via both types of tissue should not be underestimated. Our results provide basic experimental data on the skin and oral epithelia permeation for further modelling of exposure and health risk assessment.
authors.affiliation: Masaryk Memorial Cancer Institute, Hospital Pharmacy, Brno, Czech Republic. odraska@mou.cz
authors.forename: P
authors.initials: P
authors.lastname: Odraska
authors.forename: E
authors.initials: E
authors.lastname: Mazurova
authors.forename: L
authors.initials: L
authors.lastname: Dolezalova
authors.forename: L
authors.initials: L
authors.lastname: Blaha
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000493:pharmacokinetics; D003520:Cyclophosphamide / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000493:pharmacokinetics; D004817:Epidermis / Q000378:metabolism*; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D009061:Mouth Mucosa / Q000378:metabolism*; D016273:Occupational Exposure; D010539:Permeability
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin; D005472:Fluorouracil