PT - JOURNAL ARTICLE AU - Holmberg, Ann Aurell AU - Ekdahl, Anja AU - Weidolf, Lars TI - Systemic Exposure to the Metabolites of Lesogaberan in Humans and Animals: A Case Study of Metabolites in Safety Testing AID - 10.1124/dmd.113.056614 DP - 2014 Jun 01 TA - Drug Metabolism and Disposition PG - 1016--1021 VI - 42 IP - 6 4099 - http://dmd.aspetjournals.org/content/42/6/1016.short 4100 - http://dmd.aspetjournals.org/content/42/6/1016.full SO - Drug Metab Dispos2014 Jun 01; 42 AB - During preclinical and early phase clinical studies of drug candidates, exposure to metabolites should be monitored to determine whether safety conclusions drawn from studies in animals can be extrapolated to humans. Metabolites accounting for more than 10% of total exposure to drug-related material (DRM) in humans are of regulatory concern, and for any such metabolites, adequate exposure should be demonstrated in animals before large-scale phase 3 clinical trials are conducted. We have previously identified six metabolites, M1–M6, of the gastroesophageal reflux inhibitor lesogaberan. In this study, we measured exposure in humans, rats, and beagle dogs to lesogaberan and these metabolites. Plasma samples were taken at various time points after lesogaberan dosing in two clinical and three preclinical studies. Concentrations of lesogaberan and its metabolites were measured, and exposures during a single dosing interval were calculated. The parent compound and metabolites M1, M2, M4, and M5 were together shown to constitute all significant exposure to DRM in humans. Only M4 and M5 were present at levels of regulatory concern (10.6% and 18.9% of total exposure to DRM, respectively, at steady state). Absolute exposure to M5 was greater in rats during toxicology studies than the highest absolute exposure observed in humans at steady state (117.0 µmol × h/liter vs. 52.2 µmol × h/liter). In contrast, exposure to M4 in rats was less than 50% of the highest absolute exposure observed in humans. Further safety testing of this metabolite may therefore be required.