Naslov
Pharmacokinetics, brain hippocampus and cortex, and mitochondrial accumulation of a new generation of lipophilic redox-active therapeutic, Mn(III) meso tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+, in comparison with its ethyl and N-hexyl analogs, MnTE-2-PyP5+ and MnTnHex-2-PyP5+

Autori
Spasojevic, Ivan ; Weitner, Tin ; Tovmasyan, Artak ; Sheng, Huaxin ; Miriyala, Sumitra ; Leu, David ; Rajic, Zrinka ; Warner, David S. ; St. Clair, Daret ; Huang, Ting-Ting ; Batinic-Haberle, Ines

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

Izvornik
Free Radical Biology Medicine / - , 2013

Skup
SFRBM's 20th Annual meeting

Mjesto i datum
San Antonio (TX), Sjedinjene Američke Države, 20.11.2013. - 24.11.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Mn pyridylporphyrin; MnTE-2-PyP5+; MnTnHex-2-PyP5+; MnTnBuOE-2-PyP5+

Sažetak
Ortho cationic Mn(III) N-substituted pyridylporphyrins (MnPs) are efficacious in a variety of models of oxidative stress related diseases such as radiation and central nervous system injuries (stroke, subarachnoid hemorrhage, morphine tolerance, neuropathic pain) and diabetes. MnPs showed efficacy in cancer as sole agents and as radio- and chemosensitizers. to date, the best studied MnPs are hydrophilic MnTE-2-PyP5+ (log kcat(O2 􀁸􀀐) = 7.76 and E1/2 = +228 mV vs NHE), MnTDE-2-ImP5+(log kcat(O2 􀁸􀀐) = 7.83 and E1/2 = +346 mV vs NHE) and lipophilic MnTnHex-2- PyP5+(log kcat(O2 􀁸􀀐) = 7.48 and E1/2 = +314 mV vs NHE). While promising for diseases where transport across the blood-brain barrier is critical, lipophilic MnTnHex-2-PyP5+ exerts toxicity at higher doses. Its modification led to equally potent and lipophilic, but less toxic oxygen-derivatized MnTnBuOE-2-PyP5+ (log kcat(O2 􀁸􀀐) = 7.83 and E1/2 = +277 mV vs NHE). In a comprehensive pharmacokinetic study, the levels in plasma, liver, kidney, lung, heart, spleen and brain were assessed via different administration routes. Plasma oral availability (AUCoral/AUCintravenous) for MnTnBuOE-2-PyP5+ is 22%, which is nearly identical to 23% for MnTE-2-PyP5+ and 21% for MnTnHex- 2-PyP5+. Higher drug exposure was observed via subcutaneous than intravenous route and is likely related to initial drug absorption into the skin, which serves as a reservoir for slow drug release into circulation. MnTE-2-PyP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+ accumulate more in mouse heart mitochondria than in cytosol. Both lipophilic analogs, MnTnHex-2- PyP5+ and MnTnBuOE-2-PyP5+ accumulate in mitochondria ~3- fold more than hydrophilic MnTE-2-PyP5+. These data agree well with the S. cerevisiae distribution study and explain in part the higher efficacy of lipophilic MnPs. MnTnBuOE-2-PyP5+ accumulates in brain and in brain mitochondria relative to cytosol at levels comparable to MnTnHex-2-PyP5+, while under same conditions the levels of MnTE-2-PyP5+ were lower or nodetectable by LCMS/MS, respectively. Higher levels of lipophilic compounds and none of MnTE-2-PyP5+ were found in mouse hippocampus than in cortex. Both lipophilicity and pentacationic charge drive brain and mitochondrial accumulation of cationic MnPs.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Kliničke medicinske znanosti

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