A New Physiologically Based Pharmacokinetic Analysis for In Vivo Organ Disposition of Nitroxyl Spin Probes in Mice as Measured by Multisite Detection L-band ESR (MSD-LESR)

Abstract

We developed a physiologically based pharmacokinetic (PB-PK) model for spin-labeled drugs in animals and applied it for analyzing the decay curves of spin probes in the organs of mice as measured by multisite detection L-band ESR (MSD-LESR). The proposed method will be useful for not only understanding the PK features of nitroxyl radicals as spin probes but also developing spin-labeled drugs as a substitute for radioisotope-labeled drugs.

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

“…The in vivo ESR signal clearance rates of the spin probes are enhanced by reactive oxygen species (ROS), such as the hydroxyl radical and superoxide, which reduce the nitroxide radical to its hydroxylamine in the presence of the H atom donor (NADPH or glutathione) . However, since the time‐dependent ESR signal decay of the LMW spin probes is caused by organ distribution and metabolism, as well as modification to hydroxylamines (reductive reaction with ROS), it is hard to decipher the estimated redox information from the ESR spin clearance curve of the LMW spin probes . Therefore, we have noninvasively evaluated the redox status in whole animal bodies by measuring the ESR signal detected in urine using the new type of spin probe conjugated with a collagen‐like peptide that distributes to the whole blood space and recovers quantitatively from the urine.…”

“…Instrumental conditions for the measurements were as follows: frequency 9.4 GHz, microwave power 10.0 mW, modulation frequency 100 kHz, modulation amplitude width 0.1 mT, scanning time 2 min, time constant 0.03 s, and external magnetic field 330 ± 5.0 mT. ESR spectral data were collected and analyzed with a Win‐Rad data analysis system on a Windows‐PC (Radical Research, Tokyo, Japan) throughout the investigation . In in vivo AAPH‐induced oxidative stress experiments, male ddY mice (25–35 g) at the age of 5–7 weeks received i.p.…”

“…34,35 However, since the timedependent ESR signal decay of the LMW spin probes is caused by organ distribution and metabolism, as well as modification to hydroxylamines (reductive reaction with ROS), it is hard to decipher the estimated redox information from the ESR spin clearance curve of the LMW spin probes. [34][35][36][37][38][39] Therefore, we have noninvasively evaluated the redox status in whole animal bodies by measuring the ESR signal detected in urine using the new type of spin probe conjugated with a collagen-like peptide that distributes to the whole blood space and recovers quantitatively from the urine. We prepared PROXYL conjugated with the collagen-like peptide, H-(Pro-Hyp-Gly) 10 -NH 2 5, that forms a triple helical structure under physiological conditions.…”

“…ESR spectral data were collected and analyzed with a Win-Rad data analysis system on a Windows-PC (Radical Research, Tokyo, Japan) throughout the investigation. 26,38,39 In in vivo AAPH-induced oxidative stress experiments, 40,41 male ddY mice (25-35 g) at the age of 5-7 weeks received i.p. injection of AAPH at a dose of 50 mg/kg body weight and followed by i.v.…”