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Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+.

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Date
2013-05
Authors
Weitner, Tin
Kos, Ivan
Sheng, Huaxin
Tovmasyan, Artak
Reboucas, Julio S
Fan, Ping
Warner, David S
Vujaskovic, Zeljko
Batinic-Haberle, Ines
Spasojevic, Ivan
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Abstract
The cationic, ortho Mn(III) N-alkylpyridylporphyrins (alkyl=ethyl, E, and n-hexyl, nHex) MnTE-2-PyP(5+) (AEOL10113, FBC-007) and MnTnHex-2-PyP(5+) have proven efficacious in numerous in vivo animal models of diseases having oxidative stress in common. The remarkable therapeutic efficacy observed is due to their: (1) ability to catalytically remove O2(•-) and ONOO(-) and other reactive species; (2) ability to modulate redox-based signaling pathways; (3) accumulation within critical cellular compartments, i.e., mitochondria; and (4) ability to cross the blood-brain barrier. The similar redox activities of both compounds are related to the similar electronic and electrostatic environments around the metal active sites, whereas their different bioavailabilities are presumably influenced by the differences in lipophilicity, bulkiness, and shape. Both porphyrins are water soluble, but MnTnHex-2-PyP(5+) is approximately 4 orders of magnitude more lipophilic than MnTE-2-PyP(5+), which should positively affect its ability to pass through biological membranes, making it more efficacious in vivo at lower doses. To gain insight into the in vivo tissue distribution of Mn porphyrins and its impact upon their therapeutic efficacy and mechanistic aspects of action, as well as to provide data that would ensure proper dosing regimens, we conducted comprehensive pharmacokinetic (PK) studies for 24h after single-dose drug administration. The porphyrins were administered intravenously (iv), intraperitoneally (ip), and via oral gavage at the following doses: 10mg/kg MnTE-2-PyP(5+) and 0.5 or 2mg/kg MnTnHex-2-PyP(5+). Drug levels in plasma and various organs (liver, kidney, spleen, heart, lung, brain) were determined and PK parameters calculated (Cmax, C24h, tmax, and AUC). Regardless of high water solubility and pentacationic charge of these Mn porphyrins, they are orally available. The oral availability (based on plasma AUCoral/AUCiv) is 23% for MnTE-2-PyP(5+) and 21% for MnTnHex-2-PyP(5+). Despite the fivefold lower dose administered, the AUC values for liver, heart, and spleen are higher for MnTnHex-2-PyP(5+) than for MnTE-2-PyP(5+) (and comparable for other organs), clearly demonstrating the better tissue penetration and tissue retention of the more lipophilic MnTnHex-2-PyP(5+).
Type
Journal article
Subject
Blood-Brain Barrier
Mitochondria
Animals
Humans
Mice
Oxygen
Reactive Oxygen Species
Metalloporphyrins
Superoxide Dismutase
Chromatography, Liquid
Biomimetics
Signal Transduction
Oxidative Stress
Catalysis
Tandem Mass Spectrometry
Permalink
https://hdl.handle.net/10161/23283
Published Version (Please cite this version)
10.1016/j.freeradbiomed.2013.01.006
Publication Info
Weitner, Tin; Kos, Ivan; Sheng, Huaxin; Tovmasyan, Artak; Reboucas, Julio S; Fan, Ping; ... Spasojevic, Ivan (2013). Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+. Free radical biology & medicine, 58. pp. 73-80. 10.1016/j.freeradbiomed.2013.01.006. Retrieved from https://hdl.handle.net/10161/23283.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Batinic-Haberle

Ines Batinic-Haberle

Professor Emeritus of Radiation Oncology
            A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitu
Sheng

Huaxin Sheng

Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral is
Spasojevic

Ivan Spasojevic

Associate Professor in Medicine
Warner

David Samuel Warner

Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection Laboratories is dedicated to examining the pathophysiology of acute brain and spinal cord injury with particular reference to disease states managed in the perioperative or neurointensive care environments. Rodent recovery models of cerebral ischemia, traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Alphabetical list of authors with Scholars@Duke profiles.
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