Drug distribution in human skin using two different in vitro test systems: comparison with in vivo data.
OBJECTIVE
Two in vitro test systems used to study drug penetration into human skin--the Franz diffusion cell (FD-C) and the Saarbruecken penetration model (SB-M)--were evaluated, and the results were compared with data gained under analogous in vivo conditions.


METHODS
Excised human skin was used in all in vitro experiments. Flufenamic acid dissolved in wool alcohols ointment, was chosen as a model drug, and the preparation was applied using 'infinite dose' conditions. To acquire quantitative information about the drug penetration, the skin was segmented into surface parallel sections at the end of each experiment, first by tape stripping the stratum corneum (SC), and second by cutting the deeper skin layers with a cryomicrotome. The flufenamic acid was extracted from each sample and assayed by high performance liquid chromatography (HPLC). For in vivo experiments, only the tape stripping technique was used.


RESULTS
a) Drug penetration into the SC: In both in vitro test systems the total drug amounts detected in the SC were found to increase over the different incubation times. Similar conditions were obtained in vivo, but on a lower level. Using Michaelis-Menten kinetics, the m(max) value was calculated for the skin of two donors. The relations of the m(max) values for the FD-C and the SB-M closely correspond (1.26 [donor 1] and 1.29 [donor 2]). A direct linear correlation of the drug amount in the SC and the time data were found for in vivo with both in vitro test systems. b) Drug penetration into the deeper skin layers: The detected drug amounts in the deeper skin layers continuously increased with the incubation time in the SB-M, while in the FD-C, only very small drug amounts were observed after incubation times of 30 and 60 minutes. It was also noticed, that the drug amounts rose steeply at time points 3 and 6 hours. Additional studies showed a remarkable penetration of water into the skin from the basolateral acceptor compartment in the FD-C. This could explain the different drug transport into the deeper skin layers between the two in vitro test systems.


CONCLUSIONS
Both in vitro models showed comparable results for the drug penetration into the SC and a robust correlation with in vitro data. Different results were obtained for the deeper skin layers. Whether a correlation between in vitro and in vivo data is also possible here has to be investigated by further experiments.
Wagner
H
H
Dept. of Biopharmaceutics and Pharm Technology, Saarland University, Saarbruecken, Germany.
Kostka
K H
KH
Lehr
C M
CM
Schaefer
U F
UF
D000287:Administration, Topical; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D015194:Diffusion Chambers, Culture; D005260:Female; D005439:Flufenamic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D008954:Models, Biological; D012867:Skin / Q000737:chemistry / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D005439:Flufenamic Acid