title: Human skin penetration of flufenamic acid: in vivo/in vitro correlation (deeper skin layers) for skin samples from the same subject.
abstract: Previously, the interest in in vivo/in vitro correlations in the dermal field of research has increased steadily. Unfortunately, in most cases the skin from different human donors was taken for in vivo and in vitro experiments, which led to problems concerning the interindividual variability of the skin. Therefore, we established a methodology to utilize the same skin for both sets of data. In time dependency, drug amounts in the stratum corneum and the deeper skin layers were determined from eight donors using the same skin area for in vivo and the corresponding in vitro tests. Penetration experiments were carried out with the lipophilic drug flufenamic acid dissolved in wool alcohols ointment as the model formulation, which was administered to the skin under "infinite dose" conditions. At different time points prior to starting the surgery, the drug preparation was applied topically on the edges of the skin area, which was planned for excision using Finn chambers. After anesthetizing the patient and disinfecting the operation area, the incubated skin pieces were cut off first and immediately frozen to limit further drug diffusion. In vitro experiments were performed on the remaining skin flap, using two different test systems, a penetration and a permeation model. At the end of all experiments (in vivo and in vitro) the skin specimens were segmented horizontally and the drug was extracted and quantified. The in vivo and in vitro drug amounts in the stratum corneum and the deeper skin layers, respectively, were compared. The inevitable use of unknown volumes of disinfectant in vivo (medical reasons) might be the reason why a correlation failed for the stratum corneum. Nevertheless, for both in vitro test systems a direct linear correlation was found for the deeper skin layers, which showed slopes of a = 3.2272 +/- 0.3933 (penetration model vs in vivo) and a = 1.7776 +/- 0. 1926 (permeation model vs in vivo). This difference demonstrates the varying influence of the test systems and represents a factor about which in vivo and in vitro data are shifted against each other. As far as the model drug flufenamic acid is concerned, this methodology represents a tool to predict drug penetration into the deeper skin layers in vivo after carrying out corresponding in vitro experiments. Therefore, the potential is given to reduce the number of in vivo experiments, the risk for the volunteers, and the costs for the development of new drug preparations.
authors.affiliation: Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbruecken, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Wagner
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Kostka
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Schaefer
mesh_terms: D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics*; D004058:Diffusion; D004864:Equipment and Supplies; D005439:Flufenamic Acid / Q000493:pharmacokinetics*; D006801:Humans; D012867:Skin / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000893:Anti-Inflammatory Agents; D005439:Flufenamic Acid