Longitudinal plasma multi-omics characterization of nephrotoxicity in beagles after administration of propyl gallate enteric-coated tablets

Permeation enhancers (PEs) are excipients used in oral biotherapeutic formulations to facilitate the transport of bioactive compounds across the intestinal barrier and prevent their degradation. Concerns associated with the chronic use of PEs demand comprehensive approaches to elucidate potential toxicity mechanisms. A recent publication from our group reported nephrotoxicity in beagles after daily administration of enteric-coated (EC) tablets containing propyl gallate (PG) as PE. To further characterize EC-PG mediated nephrotoxicity mechanisms, we conducted a longitudinal mass spectrometry (MS)-based multi-omics analysis of dog plasma lipidome and proteome. Time-course analyses revealed elevation across multiple lipid classes and in particular species containing arachidonic acid, which may reflect EC-PG treatment-induced inflammation. At the protein level, alterations in biological processes associated with coagulation, complement activation, protein degradation and metabolism, and lipid transport and metabolism were observed. Integrative multi-omics analyses provided additional insight into toxicity mechanisms at the interface of lipids and proteins. This holistic approach highlighted lipid transport and metabolism, oxidative stress, and inflammation as altered biological processes by EC-PG administration. Altogether, longitudinal multi-omics profiling and integrative analysis provided additional mechanistic hypotheses of EC-PG induced renal toxicity demonstrating the value of such approach to investigate mechanisms relevant to drug safety.