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, enala prilat, and lisinopril, have been determined in an in vitro system usi ng rat intestine. The observed kinetic transport parameters (+/- asymp totic 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-maxima l transport concentration (K-T), the maximal transport flux (J(max)) a nd the passive permeability constant (P-m). Enalaprilat was transporte d by passive diffusional with a P-m of 0.51 (+/- 0.04) cm/h. For lisin opril 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 in testinal 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 m M, respectively. 3D structural analysis of lisinopril using molecular modelling techniques reveals that intramolecular hydrogen bond formati on is responsible for decreased carrier affinity.