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Prolonged Pharmacokinetic and Pharmacodynamic Actions of a Pegylated Parathyroid Hormone (1‐34) Peptide Fragment
Author(s) -
Guo Jun,
Khatri Ashok,
Maeda Akira,
Potts John T,
Jüppner Harald,
Gardella Thomas J
Publication year - 2017
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2917
Subject(s) - pegylation , parathyroid hormone , pharmacokinetics , chemistry , in vivo , pharmacology , peg ratio , medicine , kidney , endocrinology , biochemistry , polyethylene glycol , calcium , biology , microbiology and biotechnology , finance , economics
Polyethylene glycol (PEG) addition can prolong the pharmacokinetic and pharmacodynamic actions of a bioactive peptide in vivo, in part by impeding rates of glomerular filtration. For parathyroid hormone (PTH) peptides, pegylation could help in exploring the actions of the hormone in the kidney; e.g., in dissecting the relative roles that filtered versus blood‐borne PTH play in regulating phosphate transport. It could also lead to potential alternate forms of treatment for hypoparathyroidism. We thus synthesized the fluorescent pegylated PTH derivative [Lys 13 (tetramethylrhodamine {TMR}), Cys 35 (PEG‐20,000 Da)]PTH(1‐35) (PEG‐PTH TMR ) and its non‐pegylated counterpart [Lys 13 (TMR), Cys 35 ]PTH(1‐35) (PTH TMR ) and assessed their properties in cells and in mice. In PTHR1‐expressing HEK‐293 cells, PEG‐PTH TMR and PTH TMR exhibited similar potencies for inducing cAMP signaling, whereas when injected into mice, the pegylated analog persisted much longer in the circulation (>24 hours versus ∼ 1 hour) and induced markedly more prolonged calcemic and phosphaturic responses than did the non‐pegylated control. Fluorescence microscopy analysis of kidney sections obtained from the injected mice revealed much less PEG‐PTH TMR than PTH TMR on the luminal brush‐border surfaces of renal proximal tubule cells (PTCs), on which PTH regulates phosphate transporter function, whereas immunostained phosphorylated PKA substrate, a marker of cAMP signaling, was increased to similar extents for the two ligands and for each, was localized to the basolateral portion of the PTCs. Pegylation of a bioactive PTH peptide thus led to prolonged pharmacokinetic/pharmacodynamic properties in vivo, as well as to new in vivo data that support a prominent role for PTH action at basolateral surfaces of renal proximal tubule cells. © 2016 American Society for Bone and Mineral Research.