title: Enhanced topical and transdermal delivery of antineoplastic and antiviral acyclic nucleoside phosphonate cPr-PMEDAP.
abstract: OBJECTIVE
  Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP.
  
  
  METHODS
  In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin.
  
  
  RESULTS
  Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm(2)/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed.
  
  
  CONCLUSIONS
  Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.
authors.affiliation: Centre for New Antivirals and Antineoplastics Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic. katerina.vavrova@faf.cuni.cz
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.forename: Petra
authors.initials: P
authors.lastname: Kovaříková
authors.forename: Barbora
authors.initials: B
authors.lastname: Skolová
authors.forename: Martina
authors.initials: M
authors.lastname: Líbalová
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Roh
authors.forename: Robert
authors.initials: R
authors.lastname: Cáp
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Alexandr
authors.initials: A
authors.lastname: Hrabálek
mesh_terms: D000225:Adenine / Q000008:administration & dosage; D000279:Administration, Cutaneous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000998:Antiviral Agents / Q000008:administration & dosage*; D002208:Caproates / Q000378:metabolism*; D004123:Dimethylamines; D007851:Dodecanol; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008744:Methylamines / Q000378:metabolism*; D063065:Organophosphonates / Q000008:administration & dosage*; D010539:Permeability; D012867:Skin / Q000378:metabolism*; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002208:Caproates; D004123:Dimethylamines; D008744:Methylamines; C120401:N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D063065:Organophosphonates; C534415:dodecyl 6-(dimethylamino)hexanoate; D007851:Dodecanol; D000225:Adenine