Naslov
MnTE-2-PyP5+, a potent antioxidant and cellular redox-modulator is orally available

Autori
Kos, Ivan ; Reboucas, Julio S. ; Sheng, , Huaxin ; Warner, David S. ; Spasojevic, Ivan ; Batinic-Haberle, Ines

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Free Radical in Biology and Medicine, Vol 45./Supplement 1 / Kelvin J.A. Davies - San Diego (CA) : Elsevier, 2008, S86-s87

Skup
SFRBM's 15th Annual Meeting

Mjesto i datum
Indianapolis (IN), Sjedinjene Američke Države, 19.11.2008. - 23.11.2008

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
MnTE-2-PyP; AEOL1013; oralna bioraspoloživost;
(MnTE-2-PyP; AEOL1013; oral bioavilability)

Sažetak
Mn(III) meso-tetrakis(N-ethylpyridinium-2yl)porphyrin, MnTE-2-PyP5+ (AEOL10113) is a potent SOD mimic, peroxynitrite scavenger, and redox-regulator of cellular signaling pathways, affecting activation of transcription factors, HIF-1 , NF- B and AP-1. It markedly ameliorates oxidative stress-related diseases in animal models including radiation injury, cancer, diabetes and injuries of the central nervous systems, such as stroke, spinal cord injury, amyotrophic lateral sclerosis, and Alzheimer’ s disease. We have already shown that MnTE-2-PyP5+ localizes in mouse heart mitochondria at levels high enough to protect it against peroxynitrite-mediated injury after only single 10 mg/kg i.p. administration. A detailed mouse pharmacokinetic study followed with the same i.p. dose and showed that MnTE-2-PyP5+ distributes into all organs including brain. The maximal levels in plasma, kidney, spleen, lung, and heart were reached within first 45 minutes after injection, whereas in liver a prolonged absorption phase was observed with maximal concentration reached at 8 hours. Moreover, accumulation of the drug in brain continued for 7 days and is likely driven by the presence of negatively charged phospholipids. It has been widely accepted that, due to its excessive charges, MnTE-2-PyP5+ is not orally bioavailable. Yet, no experimental evidence in support of such presumption has ever been provided. Herein for the first time we administered MnTE-2-PyP5+ to C57BL/6J mice by oral gavage. We performed a dose-response study with 0, 5, 10, 20, 40 or 80 mg/kg. 3 mice were used per each dose. At 24 hours, liver, kidney, lung, heart, spleen and brain were excised and MnTE-2-PyP5+ levels were determined. Also plasma and hematocytes were analyzed. Method comprised reduction of MnTE-2-PyP5+ with ascorbate followed by Mn to Zn exchange and HPLC/fluorescence detection of ZnTE-2-PyP4+. Per os data obtained with 10 mg/kg dose were compared to the 10 mg/kg i.p. data previously obtained at 24 hours after injection. Levels of orally administered MnTE-2-PyP5+ in harvested organs and plasma ranged from 12% to 65% of the levels achieved with i.p. administration. Alike i.p. injection, low levels of MnTE-2-PyP were found in plasma at 24 hours. No drug was found in hematocytes. A linear dose-response relationship in MnTE-2-PyP5+ was observed in all organs. We acknowledge support from NIH U19 AI67798-01/pilot project (IBH and IK), Wallace H. Coulter Translational Partners Grant Program (IBH and IK) and NIH/NCI Duke Comprehensive Cancer Center Core Grant (5-P30-CA14236-29)(IS).

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

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