ÿþ<!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" "http://www.w3.org/TR/html4/loose.dtd"> <html> <head> <meta http-equiv="Content-Type" content="text/html; charset=iso-8859-1"> <title>EASL 2010 - Poster Presentations</title> <link rel="stylesheet" type="text/css" href="style.css"> </head> <body> <table width="750" align="center" border="0" cellspacing="0" cellpadding="0" class="MainTable"> <tr> <td><img src="http://www2.kenes.com/liver-congress/PublishingImages/top_ei.jpg" width="760" height="129" /></td> </tr> <tr> <td class="content"><h1>Poster Presentations</h1> <P><b>Session Title:</b> Category 5b. VIRAL HEPATITIS: b. HEPATITIS C - EXPERIMENTAL (VIROLOGY)<br><b>Presentation Date:</b> Apr 16, 2010</P><h2 align='left'><B>IN VITRO MODELS FOR ASSESSING THE RELATIVE RISK OF HYPERBILIRUBINEMIA ASSOCIATED WITH CYCLOPHILIN INHIBITOR THERAPY</B></h2> <p align='left'><b>S. Wring</b>*, K. Wille, C. Rewerts, R. Randolph, A. Scribner, S. Hopkins<br> <em>SCYNEXIS Inc., Research Triangle Park, NC, USA. *steve.wring@scynexis.com</em></p><br> <p align='justify'><b>Background and objectives:</b> Cyclosporin-based cyclophilin inhibitors were recently introduced into clinical testing for the treatment of chronic hepatitis C virus infection (CHC). Treatment-associated elevations in total bilirubin were reported following acute exposure of adults with CHC to some but not all analogs. Elevated bilirubin may be caused by drug-mediated inhibition of multidrug resistance protein 2 (MRP2); the primary transporter that accounts for excretion of organic anions and their conjugates including mono- and bisglucuronosyl bilirubin. The objective of the present study was to determine if a qualitative relationship exists between inhibition of MRP2 transporter activity and clinical effects on total bilirubin caused by administration of NIM811, Debio-025 and SCY-635.<br> <b><b>Methods: </b></b> Hepatobiliary accumulation, active efflux into bile canaliculi, and transporter inhibition were determined using an <i>in vitro</i> sandwich-cultured rat hepatocyte model. [D-Pen<sup>2</sup>,D-Pen<sup>5</sup>]-Enkephalin (DPDPE, a bilirubin surrogate) and Taurocholic acid (TCA) were used as substrates for rMrp2 and rBsep respectively. SCY 635, NIM811 and Debio-025 were synthesized according to published methods and purified to >90%. Structures were confirmed by proton nmr and LCMS.<br> <b><b>Results: </b></b> Uptake of all compounds into hepatocytes was dose-dependent over the concentration range 0.3-27 µM. SCY-635 was detected in hepatocytes and bile canaliculi. Debio-025, NIM811 and cyclosporine A (CsA) were detected in hepatocytes but were not effluxed into canaliculi. At 3µM accumulation for Debio-025, CsA and SCY-635 was 438 ± 47, 728 ± 266, and 144 ± 37 pmol/mg protein respectively. Values for the Biliary Excretion Index (BEI) for Debio-025 and CsA were < 1% compared to 30 ±11% for SCY-635.<br> Debio-025 and CsA completely inhibited efflux of DPDPE and attenuated efflux of TCA (BEI<sub>DPDPE</sub>, 29%; BEI<sub>DPDPE+Debio-025 or CsA</sub>, < 1%; BEI<sub>TCA</sub>, 85%; BEI<sub>TCA+Debio-025 or CsA</sub>, < 50%). Efflux of DPDPE and TCA were unaffected by SCY-635; (BEI<sub>DPDPE+SCY-635</sub>, 31%; BEI<sub>TCA+SCY-635</sub>, 84%).<br> <b><b>Conclusion: </b></b> SCY-635 demonstrated lower accumulation into hepatocytes, greater efflux into bile canaliculi, and reduced inhibition of hepatic efflux transporters than other cyclosporin-based cyclophilin inhibitors. These data are consistent with clinical observations, suggesting that the rodent hepatocyte model can be used to assess the relative risk of treatment-associated changes in total bilirubin following administration of cyclophilin inhibitors in clinical studies.<br></p> <br><a href='Session-P02-5b.htm'>Back</a><br> <p>&nbsp;</p> <p>&nbsp;</p></td> </tr> </table> </body> </html>