Abstract
During nonclinical development of an oral formulation for a glucagon-like peptide-1 (GLP-1) receptor agonist, MEDI7219, toxicology studies revealed that propyl gallate (PG), when administered in enteric-coated (EC) tablets, led to nephrotoxicity in beagles. While PG has been widely used in food and cosmetics as an antioxidant, understanding of its toxicology, metabolism, and pharmacokinetics has been rarely discussed. To elucidate the nephrotoxicity observed after administration of PG in an EC tablet formulation, we employed dog and human renal proximal tubule epithelial cells (RPTECs). We observed greater cytotoxicity to PG in dog RPTECs compared to human cells and greater increases in response to PG treatment of glutathione in human cells compared to dog cells. Glutathione elevation is a common response to detoxify xenobiotics, especially ones that produce free radicals such as PG. We hypothesize that glutathione in human RPTECs was elevated to detoxify PG, but not in dog RPTECs, leading to greater cytotoxicity for dog RPTECs. However, a subsequent study in dogs demonstrated that the oral administration of PG in a non-EC capsule did not result in renal toxicity, suggesting the physiological response to PG is modulated by the mode of absorption and a blunted glutathione response may not completely explain the PG-related renal toxicity observed in dogs. Furthermore, to characterize the pharmacokinetics and metabolism of PG we developed a 10-plex, highly sensitive and robust LC-MS/MS-based quantification method for PG and its phase-I and phase-II metabolites. The methods were employed to support preclinical dog studies and clinical study (NCT03362593).