Physicochemistry, pharmacokinetics, and pharmacodynamics of S-nitrosocaptopril crystals, a new nitric oxide donor.
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.
Jia
L
L
Chinese Academy of Medical Sciences, Beijing 100730, China. Lee.jia@ljpc.com
Young
X
X
Guo
W
W
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002216:Captopril / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002855:Chromatography, Thin Layer; D003460:Crystallization; D005243:Feces / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D020030:Nitric Oxide Donors; C060039:S-nitrosocaptopril; D002216:Captopril