Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans Grace B. Hatton, Vipul Yadav, Abdul W. Basit,

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Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans Grace B. Hatton, Vipul Yadav, Abdul W. Basit, Hamid A. Merchant Journal of Pharmaceutical Sciences Volume 104, Issue 9, Pages 2747-2776 (September 2015) DOI: 10.1002/jps.24365 Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 1 Number of publications in thousands (line plots, bottom) and percentage distribution (area plot, top) indexed in PubMed since 1965 employing use of various animal species in research. Search performed in PubMed using keywords (mice/mouse, rat, monkey, dog, guinea pig, pig, and rabbit), and filters: "title/abstract" and "other animals" under species. Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 2 Bioavailability of various drugs in human versus mouse, rat, dog, and non-human primate (NHP). Cumulative trends for all drugs are shown in graphs, whereas bubbles show correlations on classifying drugs in acidic, basic, neutral, or zwitterionic groups. Figure drawn using data from Musther et al.10 Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 3 Schematic for the gastrointestinal tract of various animal species versus human and the proportion of the total gastrointestinal length represented by the stomach, small intestine, cecum, and colon in the mouse, rat, guinea pig, rabbit, pig, and human. [adapted from Stevens207] Mice and rats data from McConnell et al.3 and human data from Davis,15 Cornes,25,26 Langman and Rowland,27 and Csendes and Burgos.28 Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 4 Mean gastrointestinal pH (in situ) profile under fed (ad libitum) state for various animal species (data from Smith,58 McConnell et al.,3 and Merchant et al.14) and Human (data from Fallingborg et al.61), where Stomach refers to pH measurements in the gastric antrum. Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 5 Correlation between the half-lives of 13 peptide drugs in pig and human gastric fluids. The drugs include, calcitonin, somatostatin, desmopressin, oxytocin, [Arg8]–vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, deslorelin, and goserelin (unpublished work). Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 6 (a) Gastrointestinal absolute water content (inset) and normalized to body weight or gut length in various animal species and human. Figure drawn using data from McConnell et al.,3 Merchant et al.,14 Gotch et al.,95 and Cummings et al.96 (b) Average bile flow rates in different species, data from Clark and Smith.97 Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 7 Degradation of new drugs TX1 (left) and AX1 (right) in human fecal versus rat cecal contents.142 Journal of Pharmaceutical Sciences 2015 104, 2747-2776DOI: (10.1002/jps.24365) Copyright © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions