Physicochemistry, pharmacokinetics, and pharmacodynamics of S‐nitrosocaptopril crystals, a new nitric oxide donor††Abbreviations: CapNO, S‐nitrosocaptopril; Cap, Captopril; RSNOs, S‐nitrosothiols; ACE, angiotensin converting enzyme; MAP, mean arterial pressure; NO, nitric oxide.
- 1 October 1999
- journal article
- Published by Elsevier BV in Journal of Pharmaceutical Sciences
- Vol. 88 (10), 981-986
- https://doi.org/10.1021/js990108g
Abstract
S-nitrosocaptopril (CapNO) has been proposed as a compound possessing capacities of both a nitric oxide (NO) donor and an inhibitor of angiotensin converting enzyme (ACE). In the present study, we characterized the physicochemical, pharmacokinetic, and pharmacological properties of the crystalline CapNO. The novel stable crystals are in a red flake form. Spectroscopic analyses of CapNO revealed its UV/visible lambda(max) and the corresponding extinction coefficients, and characteristic infrared frequencies for the N=O and S-N stretch. The NMR signals corresponding to the protons attached to the carbon (C-S) and the carbon itself were remarkably shifted downfield upon S-nitrosylation. Mass and HPLC analyses, solubility, and melting point of CapNO were determined. Simultaneous on-line analyses of pharmacodynamic and pharmacokinetic profiles of CapNO in catheterized awake rats of spontaneous hypertension (SHR) showed acute decreases in mean arterial pressure (MAP), concomitant with the corresponding increases in plasma levels of CapNO after po or iv administration. The pharmacokinetic parameters for CapNO, i.e., t(1/2), T(max), C(max), V(d), AUC, and oral bioavailability were analyzed to understand the dose-dependent potency and effective period of CapNO. The highest concentrations of oral CapNO distributed in tissues were found in kidney, liver, lung, and small intestine. CapNO was excreted predominantly via urine, and second via feces in the detectable forms of thiols and nitrogen oxide although a small portion of CapNO was found in bile. The results provide the evidence of in vivo cleavage of the S-N bond and biotransformation of CapNO.Keywords
This publication has 20 references indexed in Scilit:
- Dual actions of S-nitrosylated derivative of vasoactive intestinal peptide as a vasoactive intestinal peptide-like mediator and a nitric oxide carrierEuropean Journal of Pharmacology, 1999
- The effects of S-nitrosocaptopril on renal filtration and blood pressure in ratsEuropean Journal of Pharmacology, 1998
- Nitric Oxide and HypertensionCirculation, 1996
- S-Nitrosoglutathione Is Cleaved by the Thioredoxin System with Liberation of Glutathione and Redox Regulating Nitric OxideJournal of Biological Chemistry, 1996
- Mechanism of Nitric Oxide Release from S-NitrosothiolsJournal of Biological Chemistry, 1996
- S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular controlNature, 1996
- Differential Inhibition of Platelet Aggregation and Calcium Mobilization by Nitroglycerin and Stabilized Nitric OxideJournal of Cardiovascular Pharmacology, 1994
- New Thionitrites: Synthesis, Stability, and Nitric Oxide GenerationThe Journal of Organic Chemistry, 1994
- Nitric oxide reacts with intracellular glutathione and activates the hexose monophosphate shunt in human neutrophils: evidence for S-nitrosoglutathione as a bioactive intermediary.Proceedings of the National Academy of Sciences, 1994
- The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholineNature, 1980