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Comprehensive pharmacokinetic studies and oral bioavailability of two Mn porphyrin-based SOD mimics, MnTE-2-PyP5+ and MnTnHex-2-PyP5+.
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 articleSubject
Blood-Brain BarrierMitochondria
Animals
Humans
Mice
Oxygen
Reactive Oxygen Species
Metalloporphyrins
Superoxide Dismutase
Chromatography, Liquid
Biomimetics
Signal Transduction
Oxidative Stress
Catalysis
Tandem Mass Spectrometry
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https://hdl.handle.net/10161/23283Published Version (Please cite this version)
10.1016/j.freeradbiomed.2013.01.006Publication 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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Show full item recordScholars@Duke
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
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
Ivan Spasojevic
Associate Professor in Medicine
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
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