title: Intestinal absorption mechanism of dipeptide angiotensin converting enzyme inhibitors of the lysyl-proline type: lisinopril and SQ 29,852.
abstract: The intestinal absorption mechanism of two nonsulfhydril lysyl-proline angiotensin converting enzyme (ACE) inhibitors, lisinopril (1) and SQ 29,852 (2; [(S)-1-[6-amino-2-[[hydroxy (4-phenylbutyl)-phosphinyl]oxy[-1-oxohexyl]-L-proline) were investigated in rats using a single-pass perfusion method. Compound 2 is well absorbed from rat jejunum, whereas lisinopril absorption is relatively low. The permeability of both ACE inhibitors is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine, indicating a nonpassive absorption mechanism via the peptide carrier-mediated transport system. Compound 2 is well absorbed by a nonpassive mechanism, in parallel with a small passive component. The estimated dimensionless carrier parameters for 2 are J*max = 0.16, Km = 0.08 mM, P*c = 2.0, and P*m = 0.25; for lisinopril, passive absorption is not significant and its absorption is nonpassive: J*max = 0.032, Km = 0.082 mM, and P*c = 0.39 (where J*max is the maximal flux, Km is the Michaelis constant, P*c is the carrier permeability, and P*m is the passive permeability). These results offer a mechanistic explanation for the prolonged ACE inhibition and the low oral bioavailability of lisinopril, and for the nonlinear pharmacokinetics of 2.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
authors.forename: D I
authors.initials: DI
authors.lastname: Friedman
authors.forename: G L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D002515:Cephradine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004656:Enalapril / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007700:Kinetics; D017706:Lisinopril; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009943:Organophosphorus Compounds; D004656:Enalapril; D011392:Proline; D017706:Lisinopril; D002515:Cephradine; C054518:ceronapril