Percutaneous absorption of chemicals: developing an understanding for the treatment of disease in frogs

Abstract

The permeable nature of frog skin presents an alternative route for the delivery of therapeutic chemicals to treat disease in frogs. However, although therapeutic chemicals are often topically applied to the skin of frogs, their pharmacokinetics have rarely been reported. To provide evidence to guide both candidate drug and formulation selection, we highlight factors expected to influence percutaneous absorption through frog skin, including the anatomy and physiology of the skin and the physicochemical properties of applied therapeutic chemicals. Importantly, we also highlight the effects of the formulation on percutaneous absorption, especially the inclusion of potential penetration enhancers as excipients. Finally, we collate empirical data on the topical application of various therapeutic chemicals in postmetamorphic frogs and show that, in contrast to mammalian species, even large chemicals (i.e. >500 Da) and those with a wide range of log P values (-4 through +6) are likely to be absorbed percutaneously. Topical application in frogs thus promises a convenient and effective method for delivering systemic treatments of a diverse range of chemicals; however, further experimental quantification is required to ensure optimal outcomes.

Effects of skin region and relative lipophilicity on percutaneous absorption in the toad Rhinella marina

“…Because lipophilicity is likely to be a primary influence on transdermal absorption through frog skin (Llewelyn et al ), the chemicals included in the present study were selected to investigate the impact of increasing lipophilicity on transdermal absorption. In contrast to the findings in L. caerulea , which showed a parabolic relationship between logFlux and log P for dorsal absorption and a linear relationship for ventral absorption (Llewelyn et al ), the impact of lipophilicity on flux was consistent between skin regions in R. marina , demonstrating a decline with increasing lipophilicity.…”

“…Although it is well established that the physicochemical properties of a chemical will influence its rate and extent of absorption through mammalian skin, there is scant evidence as to how these properties influence transdermal pharmacokinetics through frog skin. Llewelyn et al () reviewed the physicochemical and skin properties that are likely to influence transdermal pharmacokinetics through frog skin, based on known frog skin physiology. Reviewing the reported outcomes for transdermal treatments and in vitro pharmacokinetic experiments in frog skin, they concluded that the relative lipophilicity of a chemical being applied to the skin, the thickness of the skin, and the skin's relative vascularization are likely to influence absorption kinetics.…”

“…It is therefore likely that transdermal pharmacokinetics in frog skin will also differ, depending on the skin region and the frog species’ primary habitat. Although there are several studies that report outcomes for transdermal therapy in frogs (for review, see Llewelyn et al ), most assess treatment success, with few transdermal pharmacokinetic studies. Further, studies investigating the effects of agricultural chemical exposure in frogs often focus on aquatic species or juvenile animals, with few studies in adult terrestrial frogs (for review, see Brühl et al ).…”

Adaption of a dermal in vitro method to investigate the uptake of chemicals across amphibian skin

“…Main determinants of dermal absorption are indicated to be molecular size (expressed as molecular volume or weight) and hydrophobicity (expressed by log P O/W ). Basically, in mammalian skin low molecular weight and high lipophilicity (up to a log P O/W of 3) lead to higher permeability coefficients [ 17 , 40 ]. In contrast to mammalian skin, the skin of X. laevis is characterized by a superficial mucus film.…”

“…Quaranta et al showed frog skin permeability being linearly and positively correlated to log P O/W (logarithm of octanol–water partition coefficient) of the applied substance, while log MW (logarithm of the molecular weight) did not predict dermal absorption [ 16 ]. Further, there is evidence from the literature that amphibian skin is permeable even to large molecules (>500 Da) and to a broader range of log P O/W (−4 to +6) compared to mammalian skin [ 17 ]. Besides physico-chemical properties of a penetrant, the other important factor influencing dermal absorption is the skin structure itself, which may differ to some extent between species adapted to different habitats, but also within one animal between different skin sites such as dorsal skin, ventral skin, or the so-called pelvic patch as a skin area specialized for fast water uptake [ 18 , 19 ].…”