ADDR Special Theme Issue “Prediction of delivery and therapeutic outcomes using animal models” Physiology and pharmacology of the brushtail possum gastrointestinal tract: Relationship to the human gastrointestinal tract Arlene McDowell a,* and Bernie J. McLeod b a b School of Pharmacy, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand AgResearch, Invermay Agricultural Centre, Private Bag 50034, Mosgiel, 9024, New Zealand * Corresponding author. Tel.: +64 3 479 7145; Fax: +64 3 479 7034. E-mail addresses: [email protected] (Arlene McDowell) [email protected] (Bernie McLeod) Abbreviations: CSM, colonic separating mechanism; GI gastrointestinal; 99m Tc, radio-labeled technetium; BSA, bovine serum albumin; LHRH, luteinizing hormone releasing hormone; DGGE, denaturing gradient gel electrophoresis; EDTA, ethylenediamine tetra-acetic acid; SDA, sodium deoxycholic acid; DTT, dithiothreitol; PSM, plant secondary metabolite. 1 Abstract Oral formulations are typically based on studies from eutherian animal models. This review introduces information relating to oral formulations for a marsupial species, the Australian brushtail possum (Trichosurus vulpecula) that have arisen from research into new methods for controlling this species, a major vertebrate pest in New Zealand. Morphologically, the gastrointestinal tract of the possums is similar to that of hindgut fermenting eutherian species, but there are some striking differences in function. Limited data suggests that the pharmacokinetics and bioavailability of administered drugs is similar to that in eutherian species, but there is some evidence that possums may have specific mechanisms for handling the intake of plant toxins and xenobiotics. The development of oral formulations for a free-ranging pest species presents several challenges above those encountered in the development of therapeutic formulations for humans and domestic animals. Use of a marsupial animal model may lead to new strategies for oral formulations in humans. Keywords: Oral delivery; marsupial; caecum, LHRH; gastrointestinal pH; transit time; Trichosurus vulpecula Contents 1. Introduction...........................................................................................................................................3 1.1. The common brushtail possum.....................................................................................................3 1.2. The brushtail possum in New Zealand..........................................................................................4 1.3 Developing oral delivery formulations for possums......................................................................5 2. Gastrointestinal tract physiology..........................................................................................................5 2.1 2.2 2.3 2.4 Morphology....................................................................................................................................5 Gastrointestinal transit...................................................................................................................8 Gastrointestinal pH......................................................................................................................10 Microflora....................................................................................................................................11 3. Barriers to oral delivery of peptides and proteins...............................................................................13 3.1 Proteolytic activity.......................................................................................................................13 3.2 Permeability.................................................................................................................................15 3.3 Epithelial cell function.................................................................................................................17 2 4. Pharmacology.....................................................................................................................................18 4.1 Metabolism of ingested toxins.....................................................................................................18 4.2 Drug pharmacokinetics in possums.............................................................................................21 5. Conclusions......................

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