title: Oral absorption of D-oligopeptides in rats via the paracellular route.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Manchester, United Kingdom.
authors.forename: Y L
authors.initials: YL
authors.lastname: He
authors.forename: S
authors.initials: S
authors.lastname: Murby
authors.forename: L
authors.initials: L
authors.lastname: Gifford
authors.forename: A
authors.initials: A
authors.lastname: Collett
authors.forename: G
authors.initials: G
authors.lastname: Warhurst
authors.forename: K T
authors.initials: KT
authors.lastname: Douglas
authors.forename: M
authors.initials: M
authors.lastname: Rowland
authors.forename: J
authors.initials: J
authors.lastname: Ayrton
mesh_terms: 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
chemical_list: D009842:Oligopeptides; D014316:Tritium