Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor

Eur J Pharm Sci. 2014 Jun 2;56:113-9. doi: 10.1016/j.ejps.2014.01.012. Epub 2014 Feb 20.


Angiotensin-converting enzyme (ACE, EC is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 μM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application.

Keywords: Hypertension; LC–MS/MS method; Lisinopril-tryptophan; Pharmacokinetic analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / chemistry
  • Angiotensin-Converting Enzyme Inhibitors / pharmacokinetics*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Caco-2 Cells
  • Catalytic Domain
  • Humans
  • Lisinopril / chemistry
  • Lisinopril / pharmacokinetics*
  • Lisinopril / pharmacology
  • Male
  • Peptidyl-Dipeptidase A / metabolism
  • Rats, Wistar
  • Tryptophan / chemistry
  • Tryptophan / pharmacokinetics*
  • Tryptophan / pharmacology


  • Angiotensin-Converting Enzyme Inhibitors
  • Tryptophan
  • Lisinopril
  • Peptidyl-Dipeptidase A