Peptide and protein drugs: The study of their metabolism and catabolism by mass spectrometry

Abstract

Peptide and protein drugs have evolved in recent years into mainstream therapeutics, representing a significant portion of the pharmaceutical market. Peptides and proteins exhibit highly diverse structures, broad biological activities as hormones, neurotransmitters, structural proteins, metabolic modulators and therefore have a significant role as both therapeutics and biomarkers. Understanding the metabolism of synthetic or biotechnologically derived peptide and protein drugs is critical for pharmaceutical development as metabolism has a significant impact on drug efficacy and safety. Although the same principles of pharmacokinetics and metabolism of small molecule drugs apply to peptide and protein drugs, there are few notable differences. Moreover, the study of peptide and protein drug metabolism is a rather complicated process which requires sophisticated analytical techniques, and mass spectrometry based approaches have provided the capabilities for efficient and reliable quantification, characterization, and metabolite identification. This review article will focus on the current use of mass spectrometry for the study of the metabolism of peptide and protein drugs.

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

“…The glycosylated LHRH compounds were shown to be less stable against metabolizing enzymes in the kidney compared to that of the liver. This was in line with the previous studies showing that the kidney plays an important role in the metabolism of LHRH derivatives (39,40). The native LHRH is degraded rapidly in blood and has a short half-life of 3-4 min (36).…”

In vivo characterisation of a therapeutically relevant self‐assembling 18F‐labelled β‐sheet forming peptide and its hydrogel using positron emission tomography

“…The concentrations observed within the liver were consistently lower than those seen in the kidney, whereas the highest concentration was seen in the bladder, confirming that the kidney is the major excretory organ for [ 18 F]FPCA‐F9 and potential radiometabolite(s). Rapid renal excretion is expected of unmodified, small peptides 12, 13…”

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

“…Such information is valuable to guide the design of new constructs with improved in vivo stability and PK properties. In addition, structure elucidation of in vivo samples also helps the assessment of potential differences in the elimination kinetics of protein product isoforms, as a biologic drug is often a collection of large protein isoforms and not a single molecular entity (45). Information gained from the in vivo measurement of various isoforms (i.e., products of a specific posttranslational modification) may guide selection or design of a new drug product with improved ADME profiles.…”