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Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and discussed at the DMDG (Drug Metabolism and Discussion Group) Peptide and Oligonucleotide ADME Workshop 2022 (2nd and 3rd of October 2022). This meeting report summarises the presentations and discussions from this workshop.The following topics were covered:Overview of the drug modality landscapeMetabolism & modellingAnalytical challengesDrug-drug interactions reports from industry working groupsRegulatory interactions.

Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 3rd online workshop of the Peptide ADME Discussion Group (3rd of February 2021). This article summarises the presentations and discussions from this workshop.The following topics were covered:Peptide drug-drug interactionsImpact of septic shock on PK and PD of the peptide selepressinMS processing software for metabolite identification of peptidesProfiling of peptides in preclinical drug developmentStrategy for immunogenicity testing of peptides In vitro stability testing of peptides for inhalation and automated LC-MS.

1. Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 1st peptide workshop of the Peptide ADME Discussion Group in Gothenburg, Sweden (15th of October 2018). This article summarises the presentations and discussions from this 1st workshop. The following topics were covered: Background science presentation on peptidases Presentation of various peptide ADME packages Peptide drug-drug interactions (DDI).

Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 2nd workshop of the Peptide ADME Discussion Group in Cambridge, UK (17th of September 2019). This article summarises the presentations and discussions from this workshop. The following topics were covered: Peptide drug-drug interactions (DDIs) Regulatory perspectives on peptide ADME studies Bioavailability of therapeutic peptides impacted by metabolism and oligomerization in the subcutaneous compartment Regulated bioanalysis of parent peptide and active metabolites by immunoaffinity LC-MS/MS Peptide radiopharmaceutical development.

Introduction: Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution., Methods: The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging., Results: The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats shows high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels., Conclusions and Advances in Knowledge: This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Xenobiotic carboxylic acids, that via their metabolites covalently modify proteins, have been associated with serious side effects in man. Such reactive metabolites may be acyl glucuronides or alternatively, the corresponding acyl-CoA thioesters. In this study, the reaction of a model xenobiotic acyl-CoA, the naproxen-CoA, with human serum albumin (HSA), was characterized by high-performance liquid chromatography employing fluorescence and mass spectrometric detection. One mM naproxen-CoA was incubated for 6 h with HSA (0.45 mM) at 37 °C in a 0.1 M phosphate buffer (pH 7.4). The tryptic digest of the reduced and alkylated protein was analyzed in order to identify the amino acids in the sequence that were covalently modified with naproxen. Fluorescent peptides, that represented naproxen-modified peptides, were characterized using HPLC–MS–MS and HPLC–MS in zoom scan mode, which provided information on the structure and the charge of the modified peptides. The naproxen-CoA reacted predominantly with lysine 199, lysine 541, and lysine 351, which was in agreement with the binding pattern that has previously been reported for the reactive acyl glucuronides and their reaction with HSA. [Copyright &y& Elsevier]