329 22 TRANSDERMAL PHARMACOLOGY OF SMALL MOLECULE CYCLIC C5a ANTAGONISTS Lavinia M. Proctor, Trent M. Woodruff, Prakirti Sharma, Ian A. Shiels and Stephen M. Taylor 1. ABSTRACT Overproduction or underregulation of the proinflammatory complement compo- nent C5a has been implicated in numerous immune and inflammatory condi- tions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous ani- mal models of inflammation following intravenous, subcutaneous, intra- peritoneal, and oral administration. In the present study the transdermal pharma- cology of PMX53 and three analogs designed with increased lipophilicity, hy- drocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administra- tion (10 mg/50 cm 2 site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (1 mg/kg i.v.). Inter- estingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (<5 ng/ml) circulating levels following topi- cal administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic ef- fects. However, increasing lipophilicity in these compounds did not result in Lavinia M. Proctor, Promics Ltd., Trent M. Woodruff, Promics Ltd. Prakirti Sharma, School of Biomedical Sciences, University of Queensland, QLD 4072, Australia. Ian A. Shiels, School of Biomedical Sciences, University of Queensland, QLD 4072, Australia. Stephen M. Taylor, Promics Ltd. and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.