ISSN:
1573-904X
Keywords:
cell culture
;
Caco-2
;
thrombin inhibitors
;
passive diffusion
;
in vitro/in vivo correlation
;
carrier-mediated transport
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Peptidomimetic thrombin inhibitors (TI), derived from L-Asp-D-Phe were examined in confluent monolayers of a human colon carcinoma cell line (Caco-2) to elucidate their transepithelial transport properties. Effect availabilities, based on activated partial thromboplastin time (aPTT) measurements in rats, after peroral administration of five TI correlated reasonably well with permeability coefficients obtained from in vitro transport studies in Caco-2 monolayers, whereas physicochemical properties, such as molecular mass, solubilities, pKa and octanol-buffer partition coefficients failed to yield meaningful relationships. Substitution of the β-carboxylic group of L-Asp leads to analogues which are mainly transported by passive diffusion, while an unsubstituted carboxylic group favours carrier-mediated active transport. The effects of concentration, temperature, competitive inhibitors and direction dependence on in vitro transport were investigated. The results obtained are compatible with a saturable carrier-mediated transport, operating parallel to a passive paracellular route. The Michaelis-Menten parameters for the active transport component (Km = 1.67 mM, Vmax = 26.5 pmol min−1 mg protein−1) indicate an involvement of the intestinal di/-tripeptide transport system for one of the TI. The Caco-2 transport model may be helpful for the design of perorally active peptidomimetics.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1016244316584
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