Spinnokinetic Analyses of Blood Disposition and Biliary Excretion of Nitric Oxide (NO)-Fe(II)-N-(Dithiocarboxy)sarcosine Complex in Rats: BCM-ESR and BEM-ESR Studies

Abstract

Nitric oxide (NO) is well known to have a wide variety of biological and physiological functions in animals. On the basis of the fact that Fe(II)-dithiocarbamates react with NO, a Fe(II)-N-(dithiocarboxy)sarcosine complex (Fe(II)-DTCS) was proposed as a trapping agent for endogenous NO. However, quantitative pharmacokinetic investigation for NO-Fe(II)-dithiocarbamate complexes in experimental animals has been quite limited. This paper describes the results on the quantitative pharmacokinetic features of a NO-Fe(II)-N-DTCS in both the blood and bile of rats following intravenous (i.v.) administration of the complex. For this purpose, we applied two in vivo methods, i.e. (1) in vivo blood circulation monitoring-electron spin resonance (BCM-ESR) which previously developed, and (2) in vivo biliary excretion monitoring-electron spin resonance (BEM-ESR). We monitored real-time ESR signals due to nitrosyl-iron species in the circulating blood and bile flow. The ESR signal due to NO-Fe(II)-DTCS was stable in biological systems such as the fresh blood and bile. In in vivo BCM- and BEM-ESR, the pharmacokinetic parameters were calculated on the basis of the two-compartment and hepatobiliary transport models. The studies also revealed that the compound is widely distributed in the peripheral organs and partially excreted into the bile. We named a kinetic method to follow spin concentrations as spinnokinetics and this method will be useful for detecting and quantifying the endogenously generated NO in Fe(II)-DTCS administered animals.

Development of Polyethylene Glycol-Conjugated Poly-S-Nitrosated Serum Albumin, a NovelS-Nitrosothiol for Prolonged Delivery of Nitric Oxide in the Blood Circulation in Vivo

“…The water-soluble iron-DTCS complex reacted with NO to give an [Fe II (DTCS) 2 (NO)] 2Ϫ (NO-iron-DTCS) complex with a three-line ESR signal (g ϭ 2.040; a N ϭ 1.27 mT) near 700 MHz and X-band frequencies at room temperature. Because the stable and water-soluble NO-iron-DTCS complex produces an intense ESR signal at room temperature, the iron-DTCS complex can be used as a spin-trapping reagent for in vivo NO assay (Yoshimura et al, 1996;Yasui et al, 2004). A three-line ESR signal (g ϭ 2.040; a N ϭ 1.27 mT) from mouse blood was observed 30 s after intravenous injection of PEG-poly SNO-BSA in mice (Fig.…”

“…PEG-poly SNO-BSA showed a sustained reduction in the MAP, whereas SNAP, GSNO, and NO-BSA induced a very short reduction. We successfully determined the NO radicals from PEG-poly SNO-BSA in vivo using an NO-trapping technique combined with ESR that has been applied to detect NO radicals in biological systems (Yoshimura et al, 1996;Yasui et al, 2004), although it is difficult to determine NO radicals in vivo because of their short half-life in vivo. This is the first direct demonstration that S-nitrosothiol releases NO radicals in the blood circulation in vivo.…”

Potential of collagen‐like triple helical peptides as drug carriers: Their in vivo distribution, metabolism, and excretion profiles in rodents

“…The triple helical peptide 1 was immediately eliminated from the blood circulation and observed under its quantification limit even after 2 min administration. The peptides present in the blood decreased in a biphasic manner and the clearance curves were fitted to the individual data on the basis of the two‐compartment PK model . Although 4 was confirmed to be stable in rat plasma for 180 min in vitro, the peptide disappeared over time in vivo.…”

“…The peptides present in the blood decreased in a biphasic manner and the clearance curves were fitted to the individual data on the basis of the two-compartment PK model. [22][23][24] Although 4 was confirmed to be stable in rat plasma for 180 min in vitro, the peptide disappeared over time in vivo. This observation indicates that 4 injected into the bloodstream was distributed to the blood and outer spaces at a steady-state and was subsequently eliminated from circulation.…”

NO spin trapping in biological systems

“…More recently, the use of other dithiocarbamate derivatives able to form water-soluble and water-insoluble complexes with iron and to bind NO was proposed by Japanese investigators (30). Water-soluble iron complexes with dithiocarbamates proved to be valuable tools for detecting NO not only in the animal tissue samples and cell cultures, but also in aqueous solutions of NO donors, such as NO synthases (NOS) (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54).…”