The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate

Extracorporeal perfusion of isolated organs of large animals – Bridging the gap between in vitro and in vivo studies

“…Two strategies may be applied in flow controlled experiments: a low flow or a high flow approach. In low flow circuits, the average flow rate and consequently the perfusion pressure, is below physiological values; however the flow still reaches and supplies the capillary bed, as demonstrated using dyes (Kietzmann et al, 1993), specimens remain viable for up to twelve hours (Cypel et al, 2008;Müller et al, 2013), and microvasculature impairment and hydrostatic edema formation (Cypel et al, 2008;Constantinescu et al, 2011;Müller et al, 2013) is reduced in comparison to high flow approaches. Systems which employ a high flow approach aim for physiological flow rates and perfusion pressures to mimic the in vivo situation more closely.…”

“…Indeed normothermia is pursued in almost all scientific implementations of the methodology (Kietzmann et al, 1993;Patan-Zugaj et al, 2012). For studies with a physiological, pharmacokinetic or pharmacologic focus (Roets et al, 1979b;Bäumer et al, 2002;Friebe et al, 2013b), the use of hypothermia would seem contra-indicated.…”

“…For specific recipes, compounds and additives to optimize the fluid's performance, refer to the respective publications. Cowie et al, 1951;Verbeke et al, 1959;Lauryssens et al, 1959Lauryssens et al, , 1960Lauryssens et al, , 1961Wood et al, 1965 Caprine Physiology Hebb and Linzell, 1951;Hardwick and Linzell, 1960;Hardwick et al, 1961Hardwick et al, , 1963Hardwick, 1965Hardwick, , 1966Linzell et al, 1967;Verbeke et al, 1957Verbeke et al, , 1968Verbeke et al, , 1972Roets et al, 1974Roets et al, , 1979a Udder Bovine Pharmacology Kietzmann et al, 1993Kietzmann et al, , 1995Kietzmann et al, , 2008Kietzmann et al, , 2010Forster et al, 1999;Kietzmann, 1999, 2001;Ehinger and Kietzmann, 2000a,b;Ehinger et al, 2006;Schumacher et al, 2011 One of the advantages associated with the use of cell free solutions is their relatively easy handling in a perfusion set-up compared with blood. The solution is readily available, even in large volumes that might be needed if an open system is the set-up of choice and variability in perfusate composition is not a concern.…”

“…This approach was most likely used in various experiments in which the publications solely mention the use of "gassed" (Kietzmann et al, 1993) or "oxygenated" (Bäumer and Kietzmann, 1999) perfusates without further specification of the oxygenation system. Perfusate reservoirs may be gassed using glassware with a sintered glass filter (Tindal, 1957), with a bubble oxygenator, which bubbles (pure) oxygen through the blood reservoir (Smith et al, 1985), or by using a rotating disc oxygenator Cameron et al, 1972), whereby several parallel discs rotate within the reservoir containing unoxygenated blood and the gas exchange occurs at the disc-blood interface.…”

“…The most frequently used gas is carbogen (95% O 2 and 5% CO 2 ) as described in Kietzmann's model (Kietzmann et al, 1993). Carbogen may be chosen when the buffer capacity of commonly used cell-free perfusion solutions depends on the presence of CO 2 (Mancina et al, 2015) or when using solutions without oxygen carriers, as these require a higher O 2 content than in room air to meet the tissues' oxygen demand.…”