Caco-2 cell permeability and stability of two d-glucopyranuronamide conjugates of thyrotropin-releasing hormone.
Caco-2 cell permeability and stability assays were used as an in vitro model to study the intestinal epithelial transport and stability of two analogues of thyrotropin-releasing hormone (TRH; Pyr-His-Pro-NH2). Peptide 1 (Pyr-His-Pro-D-glucopyranuronamide) was more permeable across the Caco-2 cell monolayer compared with the permeability of the parent TRH peptide (Papp=5.10+/-1.89x10(-6) cm/s c.f. Papp=0.147+/-0.0474x10(-6) cm/s respectively). The permeability of peptide 1 was improved threefold by attaching a 2-aminooctanoic acid moiety to the N-terminus to form peptide 2 (2-aminooctanoic acid-Gln-His-Pro-D-glucopyranuronamide) (Papp=16.3+/-2.47x10(-6) cm/s). The half-life for both peptide 1 and peptide 2 was approximately 20 min in a homogenate of Caco-2 cells compared with the half-life of TRH which is approximately 3 min. It was concluded that the permeability of peptides 1 and 2 was enhanced because of their increased stability, while the higher permeability of peptide 2 compared with peptide 1 may be attributed to its increased lipophilicity which results in enhanced passive diffusion.
Wessling
Susanne T
ST
School of Molecular and Microbial Sciences, The University of Queensland, Brisbane, Qld. 4072, Australia.
Ross
Benjamin P
BP
Koda
Yasuko
Y
Blanchfield
Joanne T
JT
Toth
Istvan
I
D000577:Amides / Q000737:chemistry*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D005965:Glucuronates / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D013973:Thyrotropin-Releasing Hormone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000577:Amides; D005965:Glucuronates; D013973:Thyrotropin-Releasing Hormone