P184 Metabolism of 14C-SRD005825 in Mouse, Rat, Dog, Monkey, and Human Hepatic Microsomes

Zhen Lou , Shire, Lexington, MA
Thiago Braga , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Devin Welty , Shire, Lexington, MA
Serene Josiah , Shire, Lexington, MA
Jody Wanta , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Sara Leitz , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Mark Gohdes , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Daniel Albaugh , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Amy Nehmer , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Donald McKenzie , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
Gang Luo , Drug Metabolism and Disposition, Covance Laboratories Inc., Madison, WI
SRD005825 (also known as SHP630) is a drug candidate developed for the treatment of autosomal dominant retinitis pigmentosa. In this study the extent of metabolism and metabolic profile of 14C-SRD005825 in vitro using mouse, rat, dog, monkey, and human hepatic microsomes was determined and the metabolites of 14C‑SRD005825 were characterized. 14C‑SRD005825 (1 and 10 mM) was incubated at 37°C with nicotinamide adenine dinucleotide phosphate (reduced form, NADPH, 1 mM) and pooled hepatic microsomes from male C57BL/6 mice, male Sprague Dawley rats, male cynomolgus monkeys and humans (male and female) for 5, 15, 30 and 45 minutes or male beagle dogs for 15, 30, 45, and 60 minutes. 14C-SRD005825 (1 mM) was also incubated with freshly prepared male and female rat [Crl:CD(SD)] hepatic microsomes and NADPH for 0 and 45 minutes. The final microsomal protein concentration was 0.5 mg/mL. Incubation samples were analyzed by HPLC with radiochemical detection. 14C-SRD005825 was metabolized by liver microsomes only when incubated in presence of NADPH, indicating that 14C-SRD005825 was chemically stable under the incubation conditions and metabolism of 14C-SRD005825 was CYP-mediated. Furthermore, 14C‑SRD005825 was metabolized in a time- and species-dependent manner. Intrinsic clearance and projected hepatic were calculated based on rate constant of 14C-SRD005825 disappearance (k) calculated from remaining 14C‑SRD005825 over incubation time, microsomal protein concentration, and yield of microsomal protein from liver. The projected hepatic clearance (mL/minute/kg) is 43.5 to 49.7 for mice, 29.3 to 41.4 for rats, 2.14 to 3.34 for dogs, 37.5 to 38.1 for monkeys, and 10.3 to 12.8 for humans. In percent of hepatic blood flow, the hepatic clearance accounts for 48.4 to 55.2 for mice (moderate), 53.2 to 75.0 for rats (moderate to high), 6.94 to 10.8 for dogs (low), 85.9 to 87.3 for monkeys (high), and 49.9 to 62.0 for humans (moderate). After incubation with rat liver microsomes for 45 minutes, the remaining 14C‑SRD005825 accounted for 3.68 and 48.9% of the total radioactivity, respectively, for the male and female, indicating a gender difference in rats. A few metabolites including M13, M8 (SRD005824), M9, and M21 were observed and characterized. Metabolic pathways were proposed.