{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bryniarski MA"],"funding":["NIDDK NIH HHS","University at Buffalo","National Institutes of Health"],"pagination":["987-996"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9907348"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["20(2)"],"pubmed_abstract":["Despite the understanding that renal clearance is pivotal for driving the pharmacokinetics of numerous therapeutic proteins and peptides, the specific processes that occur following glomerular filtration remain poorly defined. For instance, sites of catabolism within the proximal tubule can occur at the brush border, within lysosomes following endocytosis, or even within the tubule lumen itself. The objective of the current study was to address these limitations and develop methodology to study the kidney disposition of a model therapeutic protein. Exenatide is a peptide used to treat type 2 diabetes mellitus. Glomerular filtration and ensuing renal catabolism have been shown to be its principal clearance pathway. Here, we designed and validated a Förster resonance energy transfer-quenched exenatide derivative to provide critical information on the renal handling of exenatide. A combination of <i>in vitro</i> techniques was used to confirm substantial fluorescence quenching of intact peptide that was released upon proteolytic cleavage. This evaluation was then followed by an assessment of the <i>in vivo</i> disposition of quenched exenatide directly within kidneys of living rats via intravital two-photon microscopy. Live imaging demonstrated rapid glomerular filtration and identified exenatide metabolism occurred within the subapical regions of the proximal tubule epithelia, with subsequent intracellular trafficking of cleaved fragments. These results provide a novel examination into the real-time, intravital disposition of a protein therapeutic within the kidney and offer a platform to build upon for future work."],"journal":["Molecular pharmaceutics"],"pubmed_title":["Defining the Intravital Renal Disposition of Fluorescence-Quenched Exenatide."],"pmcid":["PMC9907348"],"funding_grant_id":["NIH P30DK079312-13","P30 DK079312","R01 DK091623","1R01DK091623-06"],"pubmed_authors":["Campos-Bilderback SB","Fraser-McArthur J","Yacoub R","Sandoval RM","Molitoris BA","Bryniarski MA","Ruszaj DM","Yee BM","Chaves LD","Morris ME"],"additional_accession":[]},"is_claimable":false,"name":"Defining the Intravital Renal Disposition of Fluorescence-Quenched Exenatide.","description":"Despite the understanding that renal clearance is pivotal for driving the pharmacokinetics of numerous therapeutic proteins and peptides, the specific processes that occur following glomerular filtration remain poorly defined. For instance, sites of catabolism within the proximal tubule can occur at the brush border, within lysosomes following endocytosis, or even within the tubule lumen itself. The objective of the current study was to address these limitations and develop methodology to study the kidney disposition of a model therapeutic protein. Exenatide is a peptide used to treat type 2 diabetes mellitus. Glomerular filtration and ensuing renal catabolism have been shown to be its principal clearance pathway. Here, we designed and validated a Förster resonance energy transfer-quenched exenatide derivative to provide critical information on the renal handling of exenatide. A combination of <i>in vitro</i> techniques was used to confirm substantial fluorescence quenching of intact peptide that was released upon proteolytic cleavage. This evaluation was then followed by an assessment of the <i>in vivo</i> disposition of quenched exenatide directly within kidneys of living rats via intravital two-photon microscopy. Live imaging demonstrated rapid glomerular filtration and identified exenatide metabolism occurred within the subapical regions of the proximal tubule epithelia, with subsequent intracellular trafficking of cleaved fragments. These results provide a novel examination into the real-time, intravital disposition of a protein therapeutic within the kidney and offer a platform to build upon for future work.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Feb","modification":"2026-06-03T12:38:02.597Z","creation":"2025-04-05T10:45:27.232Z"},"accession":"S-EPMC9907348","cross_references":{"pubmed":["36626167"],"doi":["10.1021/acs.molpharmaceut.2c00671"]}}