IPPSF

Further specimens in use are the perfused cow udder, the porcine forelimb, and the isolated perfused porcine skin flap (IPPSF) [55-57], While the first two require the sacrifice of the animal, the last one can be isolated surgically from the abdomen of the pigs, which afterwards can be returned to their prior disposition [49],... 

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). 

Preliminary studies using the IPPSF have shown that compounds such as the cancer chemotherapeutic agents cisplatin and carboplatin and the antibiotics tetracycline and doxycycline readily distribute into the skin following intravascular administration. Also, compounds such as parathion, 1-aminobenzo-triazole (ABT), and 25-hydroxyvitamin D are bioactivated in the skin following intravascular administration in the IPPSF. This demonstrates a role for the IPPSF as an ideal experimental model for studying the disposition of xenobiotics that are... 

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... 

Riviere JE, Williams PL, Hillman R, Mishky L. Quantitative prediction of transdermal iontophoretic delivery of arbutamine in humans using the in vitro isolated perfused porcine skin flap (IPPSF). J Pharm Sci 1992 81 504-7. 

For some pesticides, in vivo and in vitro data are comparable. An excellent example is the dermal ab.sorption of malathion (6.8% dose at 24 hr and 8.2% dose at 5 days) in human volunteers (Feidmann and Maibach, 1974 Maibach and Feidmann, 1974), which is comparable to in vitro absorption (8.77% dose at 24 hr) in human skin (Wester et al., 1996), in vivo absorption of malathion in Yorkshire pigs (5.2% at 6 days) (Carver and Riviere, 1989), as well as predicted IPPSF absorption (5.9%) (Williams et al., 1990). 

Despite the limited amounts absorbed, they were sufficient to cause morphological and biochemical changes in the IPPSFs. This finding clearly indicates the importance of the phenomenological dilemma introduced earlier, in which although minimal. systemic absorption and thus systemic toxicity would be expected to occur, sufficient paraquat was absorbed across the stratum comeum into the epidermis/ dermis to illicit a local dermatotoxic effect. The potential for local toxicological effects is present for topical dosing of these pesticides. 

Montciro-Riviere, N. A., Bowman, K. F., Scheidl, V. J and Riviere, J. E. (1987). The isolated pcrfu.scd porcine skin flap (IPPSF). II. Ultrastruciural and histological charactenzation of epidermal viability. In Vitro Toxicol. I, 241-252. 

William.s, P, L.. Carver, M. R. and Riviere, J. E. (1990), A physiologically relevant pharmacokineiic model of xenobiotic percutaneous absorption utilizing the i.soIatcd perfused porcine skin flap (IPPSF). J. Phtirm. Sci 79, 305-311,... 

Quantitative Structure-Activity Relationship (QSAR) IPPSF Models..39... 

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 ... 

Reports have sporadically appeared in the literature on perfused pieces of animal and human skin used in various studies (Feldberg and Paton, 1951 Kjaersgaard, 1954 Hiemickel, 1985 Kietzmann etal., 1991) however, none have ever been optimized or validated for percutaneous absorption studies. In contrast, a human—rat sandwich skin flap on athymic rats has been employed to study dermal absorption of various compounds (Krueger etal., 1985 Wojciechowski etal., 1987 Silcox et al., 1990). The IPPSF is the focus of the present chapter. 

Figure 3.2 Temperature- and humidity-controlled chamber used to maintain IPPSF viability and environmental conditions throughout an experiment.

There have been three types of studies conducted in the IPPSF toxicology, percutaneous absorption (including biotransformation and pharmacokinetic modeling), and cutaneous drug distribution (drug administered by intraarterial infusion). The first two are discussed in this chapter. 

The IPPSF model offers many unique advantages. First, it allows confirmation that cutaneous exposure to a penetrating molecule actually occurred. Second, it allows quantitation of this exposure and subsequent correlation to severity of toxicity observed. Finally, it would allow the development of linked toxicokinetic-toxico-dynamic models to be developed, which should shed insight into the mechanisms of cutaneous toxicity. 

Figure 3.3 Typical IPPSF venous flux profile for a percutaneous absorption experiment (mean SD) depicting naphthalene, dodecane, and hexadecane absorption after topical dosing from JP-8 jet fuel.

Percutaneous absorption in the IPPSF was correlated (r 0.8) to in vivo human absorption for live diverse compounds (Wester et al., 1998). The IPPSF estimate for absorption used was the amount absorbed into the perfusate plus the amounts penetrated into the skin. Comparative absorption values (% dose, mean + SD) were as follows ... 

Rgure 3.4 IPPSF-predicted vs. human availabilities for 16 compounds for which comparable experimental conditions (dose/unit area, vehicle) for both data sets were available. 

A similar analysis of all available data in the IPPSF for which comparable (similar dose, vehicle) hnman dermal absorption data were also available is depicted in Figure 3. 4. As can be seen, there is a high level of correlation = 0.91) between... 

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