The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: in situ rat intestinal perfusion studies.
LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single-pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis-Menten process in parallel with a linear process. The estimated parameters were: J(max) = 26.7 x 10(-5) micromol/(cm(2)-s), K(m) = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly-Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable.
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
André H
AH
Eriksson
Manthena V S
MV
Varma
Everett J
EJ
Perkins
Cheryl L
CL
Zimmerman
D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D027981:Symporters / Q000037:antagonists & inhibitors / Q000502:physiology*
C503966:2-((2'-amino)propionyl)aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D004151:Dipeptides; D018690:Excitatory Amino Acid Agonists; D000074011:Peptide Transporter 1; D011355:Prodrugs; D027981:Symporters; C004194:glycylsarcosine; D000409:Alanine; C104753:eglumetad