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Table 1. In-vitro metabolic stability half-lives and dehalogenation of iodinated obestatinTissueHalf-life (min) [% dehalogenation]NIP a MIP (Tyr) b DIP (Tyr) c DIP (His) dPlasma 16.8 14.7 [14.4] 26.9 [59.8] 16.7 [69.3]Liver 15.7 41.5 [9.2] 14.2 [13.5] 18.4 [37.2]Kidney 7.0 10.9 [0.0] 18.8 [3.5] 13.2 [2.9]a NIP = non iodinated peptideb MIP (Tyr)= mono-iodinated peptide on the tyrosine residuec DIP (Tyr) = di-iodinated peptide on the tyrosine residueAdditionally, d DIP (His)=significantdi-iodinateddehalogenationpeptide on thewashistidineobservedresiduefor the iodinated derivatives as well,especially for (DIP (His))-obestatin incubated in plasma (Table 1). Iodine atom(s) removalin plasma was found to increase in the following order: MIP (Tyr), DIP (Tyr) and DIP(His). The percentage of peptide degradation solely attributed to deiodinase activity wasestimated to reach up to 69.3%, the remainder being proteolysis. In vitro dehalogenationwas also observed in liver and kidney homogenates, although to a lesser extent whencompared to plasma. Especially when the percentage of deiodination was found to be ratherhigh, several metabolites arising from a combination of dehalogenation and proteolysiswere observed as well.In conclusion, this study demonstrated that the pharmacokinetic profile of tyrosineandhistidine-iodinated mouse obestatin derivatives is not only severely compromisedthrough rapid degradation by systemic proteolytic enzymes, but also by dehalogenases.Also, the site-specificity of the proteases is altered by incorporation of iodine atoms.Hence, their use to predict the in vivo pharmacokinetics of unmodified peptide isquestionable.AcknowledgmentsThis research is funded by a PhD grant (no. 73402) of “Agency for Innovation by Science andTechnology in Flanders (IWT)”.References1. Thomas, S.R., McTamney, P.M., Adler, J.M., LaRonde-LeBlanc, N., Rokita, S.E. J. Biol. Chem.284, 19659-19667 (2009).2. Friedman, J.E., Watson, J.A., Lam, D.W.H., Rokita, S.E. J. Biol. Chem. 281, 2812-2819 (2006).3. Dentice, M., Ambrosio, R., Salvatore, D. Expert Opin. Ther. Targets 13, 1363-1373 (2009).4. Goldberg, E.R., Cohen, L.A. Bioorg. Chem. 21, 41-48 (1993).5. Solis-S, J.C., Villalobos, P., Orozco, A., Valverde-R, C. J. Endocrinol. 181, 385-392 (2004).6. Vergote, V., Van Dorpe, S., Peremans, K., Burvenich, C., De Spiegeleer, B. Peptides 29, 1740-1748(2008).503