Suitability of enalapril as a probe of the dipeptide transporter system: in vitro and in vivo studies.
OBJECTIVE
Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS.


METHODS
The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range.


RESULTS
In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption.


CONCLUSIONS
The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.
Morrison
R A
RA
Bristol-Myers Squibb Pharmaceutical Research Institute (BMS-PRI), Princeton, New Jersey 08540, USA.
Chong
S
S
Marino
A M
AM
Wasserman
M A
MA
Timmins
P
P
Moore
V A
VA
Irwin
W J
WJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002433:Cefaclor / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics; D010539:Permeability; D011392:Proline / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D009943:Organophosphorus Compounds; D002433:Cefaclor; D004656:Enalapril; D011392:Proline; C054518:ceronapril