Swaan P W, Stehouwer M C, Tukker J J
Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences (UIPS), University of Utrecht, The Netherlands.
Biochim Biophys Acta. 1995 May 24;1236(1):31-8. doi: 10.1016/0005-2736(95)00030-7.
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.
基于三种底物的三维（3D）结构数据，解释了它们对肠道肽载体的亲和力。使用大鼠肠道在体内系统中测定了三种ACE抑制剂（依那普利、依那普利拉和赖诺普利）的动力学转运参数。依那普利观察到的动力学转运参数（±渐近标准误差）为：半数最大转运浓度（KT）为0.81（±0.23）mM，最大转运通量（Jmax）为0.58（±0.37）μmol/h·cm²，被动渗透常数（Pm）为0.56（±0.04）cm/h。依那普利拉通过被动扩散转运，Pm为0.51（±0.04）cm/h。对于赖诺普利，KT、Jmax和Pm的动力学转运参数分别为0.38（±0.19）mM、0.12（±0.07）μmol/h·cm²和0.18（±0.02）cm/h。基于ACE抑制剂抑制头孢氨苄转运速率的能力，评估了它们对肠道肽载体的亲和力。依那普利、依那普利拉和赖诺普利的抑制常数（Ki）分别为0.15、0.28和0.39 mM。使用分子建模技术对赖诺普利进行的3D结构分析表明，分子内氢键的形成导致载体亲和力降低。
