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. 2024 Apr 13;25(8):4318.
doi: 10.3390/ijms25084318.

Evaluation of Ouabain's Tissue Distribution in C57/Black Mice Following Intraperitoneal Injection, Using Chromatography and Mass Spectrometry

Denis A Abaimov  1 , Rogneda B Kazanskaya  1   2 , Ruslan A Ageldinov  3 , Maxim S Nesterov  3 , Yulia A Timoshina  1   4 , Angelina I Platova  5 , Irina J Aristova  2   6 , Irina S Vinogradskaia  7 , Tatiana N Fedorova  1 , Anna B Volnova  2   6 , Raul R Gainetdinov  6   8 , Alexander V Lopachev  1   6
Affiliations

Evaluation of Ouabain's Tissue Distribution in C57/Black Mice Following Intraperitoneal Injection, Using Chromatography and Mass Spectrometry

Denis A Abaimov et al. Int J Mol Sci. .

Abstract

Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs' applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC-MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: Cmax = 882.88 ± 21.82 ng/g; Tmax = 0.08 ± 0.01 h; T1/2 = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: Cmax = 145.24 ± 44.03 ng/g (undetectable at 60 min); Tmax = 0.08 ± 0.02 h; T1/2 = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: Cmax = 1072.3 ± 260.8 ng/g; Tmax = 0.35 ± 0.19 h; T1/2 = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: Cmax = 2558.0 ± 382.4 ng/g; Tmax = 0.35 ± 0.13 h; T1/2 = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS.

Keywords: blood plasma; brain; brain–blood barrier; cardiac tissue; cardiotonic steroids; digoxin; kidney; liver; ouabain.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure A1
Figure A1
Demonstration chromatogram of a standard sample of ouabain (A) at a concentration of 125 ng/mL for daughter ions with m/z 403.2 and an internal standard (D2) of ouabain at a concentration of 100 ng/mL (B) for daughter ions with m/z 376.15.
Figure A2
Figure A2
Second-order mass spectra for ouabain (A) and D2–ouabain (B).
Figure A3
Figure A3
Calibration function of ouabain in model solutions, obtained using HPLC–MS/MS triple quadrupole method. X axis—ouabain concentration, ng/mL.
Figure 1
Figure 1
Structures of the CTS ouabain (A) and digoxin (B).
Figure 2
Figure 2
Averaged pharmacokinetic curves representing the elimination of ouabain from (A) blood plasma, (B) cardiac tissue, (C) kidney tissue, and (D) liver tissue following intraperitoneal injection of ouabain at a dose of 1.25 mg/kg bodyweight to C57/black mice. All the curves are superimposed in (E). X-axis—time from injection (min); y-axis—concentration (ng/g); n = 6. All the concentrations are presented as mean ± SD. Error bars were omitted in (E) to increase readability.
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