Isolated perfused porcine skin flap models

Riviere et al. (1999) used the isolated perfused porcine skin flap model to study absorption and disposition of JP-8. The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A and JP-8 jet fuels were assessed by monitoring the absorptive flux of the marker components 14C naphthalene and 3H dodecane simultaneously. Absorption of 14C hexadecane was estimated from JP-8. Data were not reported in absolute amounts or concentrations. Instead, the objectives were to determine the relative absorption of the individual marker components from jet fuel, and the effect of a specific jet fuel s composition on the absorption of a specific marker. Having evaluated the absorption of only three of the 228 major nonadditive hydrocarbon constituents of the fuels, the authors stated that this is insufficient information to conduct risk assessments on jet fuels. However, the authors conclusions are informative. Naphthalene penetrated the skin more rapidly than dodecane or hexadecane, but the latter compounds had a larger fraction of the dose deposited in the skin. There were also differences in naphthalene and dodecane absorption and skin deposition between the fuels. These findings reinforce the difficulty of predicting risk for complex mixtures such as jet fuels. 

J. E. Riviere, K. F. Bowman, and N. A. Monteiro-Riviere. The isolated perfused porcine skin flap (IPPSF). I. A novel in vitro model for percutaneous absorption and cutaneous toxicology studies. Fundam. Appl. Toxicol. 7 444—453 (1986). 

Riviere, J.E. Monteiro-Riviere, N.A. Wilhams, P.L. The isolated perfused porcine skin flap as an in vitro model for predicting transdermal pharmacokinetics. Eur. J. Phar-mac. Biopharmac. 1995, 41, 152-162. 

There are several perfused skin preparations with an intact functional microvasculature. The major advantage of such a perfused system is that subsequent systemic influences on absorbed chemical are not present, yet the tissue is fully functional with an intact microcirculation unlike simpler in vitro models. The perfused rabbit ear model, perfused pig ear model, in situ sandwich skin flap in athymic rats, and the hybrid rat-human sandwich flap have been developed [8], but each intuitively has severe limitations. The isolated perfused porcine skin flap (IPPSF) developed in our laboratory is a unique ex vivo skin preparation that has an intact functional cutaneous microcirculation. Predictions from IPPSF studies have correlated well with in vivo absorption... 

Williams PL, Carver MP, Riviere JE. A physiologically relevant pharmacokinetic model of xenobiotic percutaneous absorption utilizing the isolated perfused porcine skin flap (IPPSF). J Pharm Sci 1990 79 305-11. 

Isolated perfused skin models, such as the isolated perfused porcine skin flap (IPPSF) developed in our laboratory, may be the missing link in the hierarchy of classic in vitro and in vivo models. Primary advantages of isolated perfused systrans include the following ... 

In order to assess the efficacy of electroporation in a model system that closely resembles human clinical use, the transdermal delivery of LHRH was studied using the isolated perfused porcine skin flap (IPPSF) model. The IPPSF model is a viable and vascularized in vitro system that was developed to quantify percutaneous absorption and cutaneous toxicity (Riviere et al, 1994 Riviere and Monteiro-ffiviere, 1991). The model has been used successfifily to predict human iontophoretic delivery ofarbutamine (Riviere et al, 1992b), to assess iontophoretic-induced skin irritation (Monteiro-Riviere, 1990), and to characterize the pathway of compound delivery across the skin (Monteiro-Riviere et al, 1994). Of particular relevance to the studies described here are our studies, in vivo and using the IPPSF model, of the iontophoretic deliveiy of LH (Heit et al., 1993, 1994). These studies have shown that LHRH is an excellent model peptide with which to... 

Riviere et aL (1995) studied the toxicokinetics of topically administered C-sulfur mustard in their isolated perfused porcine skin flap (IPPSF) model to support the correlation between eritical steps in the vesication process and concentrations of the agent in different skin regions. About 90% of the radioactivity was not recovered due to evaporation of the agent from the skin. No attempts were made to avoid evaporation, since occlusion was not considered to be a realistic exposure condition. Absorption mainly occurred within the first hour after application, with the majority of the absorbed radioactive dose either in the skin or venous blood stream of the IPPSF. A large fraction of the measured radioactivity was probably not intact sulfur mustard however, the identity of the radioactive species was not established. A multicompartmental toxicokinetic model was developed to predict penetration into and distribution within the IPPSF. The authors report that sulfur mustard decreased the vascular volume of distribution in IPPSF in a dose dependent way, a phenomenon that should be incorporated into the toxicokinetic model. 

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