MOLECULAR MECHANISM FOR THE RELATIVE BINDING-AFFINITY TO THE INTESTINAL PEPTIDE CARRIER - COMPARISON OF 3 ACE-INHIBITORS - ENALAPRIL, ENALAPRILAT, AND LISINOPRIL

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 vitro system using rat intestine. The observed kinetic transport parameters (+/- asymptotic standard error) of enalapril are: 0.81 (+/- 0.23) mM, 0.58 (+/- 0.37) mu mol/h per cm(2), and 0.56 (+/- 0.04) cm/h for the half-maximal transport concentration (K-T), the maximal transport flux (J(max)) and the passive permeability constant (P-m). Enalaprilat was transported by passive diffusional with a P-m of 0.51 (+/- 0.04) cm/h. For lisinopril the kinetic transport parameters were 0.38 (+/- 0.19) mM, 0.12 (+/- 0.07) mu mol/h per cm(2), and 0.18 (+/- 0.02) cm/h for K-T, J(max), and P-m, 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 (K-i) 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.