title: Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors: enalapril, enalaprilat, and lisinopril.
abstract: The affinity of three substrates for the intestinal peptide carrier is explained based on their three-dimensional (3D) structural data. The kinetic transport parameters of three ACE-inhibitors, enalapril, enalaprilat, and lisinopril, have been determined in an in vivo system using rat intestine. The observed kinetic transport parameters (+/- asymptotic standard error) of enalapril are: 0.81 (+/- 0.23) mM, 0.58 (+/- 0.37) mumol/h per cm2, and 0.56 (+/- 0.04) cm/h for the half-maximal transport concentration (KT), the maximal transport flux (Jmax) and the passive permeability constant (Pm). Enalaprilat was transported by passive diffusional with a Pm of 0.51 (+/- 0.04) cm/h. For lisinopril the kinetic transport parameters were 0.38 (+/- 0.19) mM, 0.12 (+/- 0.07) mumol/h per cm2, and 0.18 (+/- 0.02) cm/h for KT, Jmax, and Pm, respectively. The affinity of the ACE-inhibitors for the intestinal peptide carrier has been evaluated based on their ability to inhibit the transport rate of cephalexin. The inhibition constants (Ki) of enalapril, enalaprilat and lisinopril were 0.15, 0.28 and 0.39 mM, respectively. 3D structural analysis of lisinopril using molecular modelling techniques reveals that intramolecular hydrogen bond formation is responsible for decreased carrier affinity.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences (UIPS), University of Utrecht, The Netherlands.
authors.forename: P W
authors.initials: PW
authors.lastname: Swaan
authors.forename: M C
authors.initials: MC
authors.lastname: Stehouwer
authors.forename: J J
authors.initials: JJ
authors.lastname: Tukker
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D015820:Cadherins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002506:Cephalexin / Q000378:metabolism; D004656:Enalapril / Q000378:metabolism; D015773:Enalaprilat / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D017706:Lisinopril / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015820:Cadherins; D002352:Carrier Proteins; C490586:Cdh17 protein, rat; D026901:Membrane Transport Proteins; C067802:intestinal peptide-proton cotransporter; D004656:Enalapril; D017706:Lisinopril; D015773:Enalaprilat; D002506:Cephalexin