P233 Evaluation of SRD005825 as a Substrate and Inhibitor of a Panel of Human Drug Transporters

Gang Luo , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Devin Welty , Shire, Lexington, MA
Serene Josiah , Shire, Lexington, MA
Manuela Gast , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Deborah Lee , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Ryan Keehn , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Daniel Albaugh , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Donald McKenzie , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Zhen Lou , Shire, Lexington, MA
SRD005825 (also known as SHP630) is a drug candidate developed for the treatment of autosomal dominant retinitis pigmentosa. In this study, SRD005825 was evaluated for its potential interactions with a panel of key human transporters including Organic Anion Transporter (OAT) 1 and OAT3, Organic Cation Transporter (OCT) 2, Organic Anion Transporting Polypeptide (OATP) 1B1, OATP1B3 and OATP2B1, and Multidrug and Toxin Extrusion (MATE) 1, MATE2‑K, P‑glycoprotein (P‑gp), and Breast Cancer Resistance Protein (BCRP). Transiently transfected HEK293 cells were used for uptake assays with incubation for 2 minutes (MATE1 only) or 5 minutes (the remaining uptake transporters). Caco-2 cells were used for efflux assays of P-gp and BCRP with incubation for 2 hours. For substrate assays, 14C‑SRD005825 was used at 1 and 10 µM. For inhibition assays, SDR005825 was used up to 200 µM. Probe substrates and known inhibitors were included for all assays as positive controls. The fold uptake of 14C-SRD005825 over vector control was ≤1.26 by OAT1, ≤0.804 by OATP1B1, ≤0.971 by OATP1B3, ≤0.802 by MATE1, and ≤1.20 by MATE2‑K. The fold uptake of 14C-SRD005825 over vector control was up to 4.40 by OAT3, up to 3.52 by OCT2, and up to 3.09 by OATP2B1; however, the fold uptake was not decreased by selective inhibitors. SRD005825 showed inhibition of OAT3, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2‑K, but not OAT1 and OATP2B1. The IC50 value was 2.67 µM for OAT3, 108 µM for OATP1B1, 37.1 µM for MATE1, and 41.5 µM for MATE2-K. IC50 value was not determined for OCT2 and OATP1B3, but estimated to be approximately 100 µM. In Caco-2 cells 14C‑SRD005825 had efflux ratios ≤1.59 indicating that SRD005825 was not a substrate of P-gp or BCRP. SRD005825 showed inhibition of P-gp and BCRP. The IC50 value was 33.0 µM for BCRP. IC50 value was not determined for P‑gp, but estimated to be approximately 100 µM. In summary, 14C‑SRD005825 did not appear to be a substrate of transporters tested under the conditions of the study. SRD005825 showed moderate or weak inhibition of OAT3, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, and BCRP, but not OAT1 and OATP2B1.