Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis?
A Baumann, D Tuerck, S Prabhu, L Dickmann… - Drug discovery today, 2014 - Elsevier
A Baumann, D Tuerck, S Prabhu, L Dickmann, J Sims
Drug discovery today, 2014•ElsevierHighlights•PK-related aspects of potential vacuolization after administration of PEG
proteins.•PK of PEG proteins is initially driven by the protein and its conjugated PEG.•PK
governed by PEG-related mechanisms after cleavage of PEG.•PEG protein is cleared in one
pathway directly by the kidney (faster).•Slow pathway based on nonspecific uptake of the
PEG and/or PEG proteins into cells.The pharmacokinetics (PK), metabolism and
biodistribution of polyethylene glycol (PEG) in PEGylated proteins are important to …
proteins.•PK of PEG proteins is initially driven by the protein and its conjugated PEG.•PK
governed by PEG-related mechanisms after cleavage of PEG.•PEG protein is cleared in one
pathway directly by the kidney (faster).•Slow pathway based on nonspecific uptake of the
PEG and/or PEG proteins into cells.The pharmacokinetics (PK), metabolism and
biodistribution of polyethylene glycol (PEG) in PEGylated proteins are important to …
Highlights
- PK-related aspects of potential vacuolization after administration of PEG proteins.
- PK of PEG proteins is initially driven by the protein and its conjugated PEG.
- PK governed by PEG-related mechanisms after cleavage of PEG.
- PEG protein is cleared in one pathway directly by the kidney (faster).
- Slow pathway based on nonspecific uptake of the PEG and/or PEG proteins into cells.
The pharmacokinetics (PK), metabolism and biodistribution of polyethylene glycol (PEG) in PEGylated proteins are important to understand the increased cellular vacuolation reported in various tissues in animals. The tissue distribution profile of PEGylated proteins and ‘metabolic’PEG is guided largely by absolute PEG load, PEG molecular weight and, where applicable, receptor-mediated uptake via the protein moiety. High molecular weight PEGs show slow renal clearance, and consequently have a greater potential to accumulate within cells. The intracellular nonbiodegradable PEG can accumulate within the lysosome ultimately causing distension and vacuolation observed by standard histological examinations. Improved bioanalytical methodologies will contribute to the identification of specific PK parameters including distribution behavior to support development of PEGylated proteins as therapeutics.
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