Oral absorption of D-oligopeptides in rats via the paracellular route.
OBJECTIVE
This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers.


METHODS
The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [3H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations.


RESULTS
As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailability.


CONCLUSIONS
This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.
He
Y L
YL
Department of Pharmacy, University of Manchester, United Kingdom.
Murby
S
S
Gifford
L
L
Collett
A
A
Warhurst
G
G
Douglas
K T
KT
Rowland
M
M
Ayrton
J
J
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008970:Molecular Weight; D009842:Oligopeptides / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D009842:Oligopeptides; D014316:Tritium