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Comprehensive Pharmacokinetic Studies and Biodistribution of Two Cationic Mn Porphyrin-Based Catalysts, MnTE-2-PyP and MnTnHex-2-PyP: Plasma and Organ Oral Availability, Mitochondrial, Cytosolic, Whole Brain, Hippocampus and Cortex Distribution Tin Weitner, Huaxin Sheng, Sumitra Miriyala, David Leu, Artak Tovmasyan, Ivan Kos, Julio S Reboucas, Ping Fan, Zeljko Vujaskovic, Ines Batinic-Haberle, Ting-Ting Huang, Daret St Clair, David S Warner, and Ivan Spasojevic Duke University, University of Kentucky, Stanford University, GRECC, VA Palo Alto HCS, University of Zagreb, Croatia Universidade Federal da Paraiba, Brazil Cationic, ortho Mn(III) N-substituted pyridylporphyrins (MnPs) are efficacious in animal models of oxidative diseases, where they act as catalysts and redox-regulators of cellular transcriptional activity. MnTE-2-PyP (MnEt) and MnTnHex-2-PyP (MnHex) have similar redox-based properties, identical charge, and are thus among the most potent SOD mimics and peroxynitrite reductants. Yet, they differ greatly with regards to lipophilicity, bulkiness, and shape. These differences translate into differences in their bioavailability and in turn therapeutic potential. Mouse pharmacokinetic studies [MnEt=10 mg/kg (iv, ip, oral), MnHex=0.5 mg/kg (iv) and 2 mg/kg (ip, oral)] demonstrate their oral availability (plasma AUCORAL/plasmaAUCIV) of 23% for MnEt and 20% for MnHex. Organ oral availability (AUC of plasma and liver, kidney, spleen, heart, lung, brain), expressed as AUCORAL/AUCIP (where AUCIP is ~84% of AUCIV for both compounds), is 13%, and 33% for MnEt and MnHex. More hydrophilic MnEt favors aqueous plasma environment, whereas the more lipophilic MnHex distributes more in vital organs than MnEt (MnHex/MnEt=2.5). In a separate mouse study, both MnPs prefer heart mitochondria (MITO) to cytosol (CYT) (5 days subcutaneous (sc) 2 mg/kg bid) which is in agreement with their beneficial effects in mitochondrial disorders. The cardiac MITO/CYT ratio reflects the distribution pattern seen with organs: 1.6 and 3.6 for MnEt and MnHex (MnHex/MnEt=2.2). Trend in mouse brain distribution (5 days sc 2 mg/kg bid) of 13 nM and 18 nM for MnEt and MnHex (MnHex/MnEt=1.4) is in agreement with overall organ and mitochondrial distribution. The hippocampus levels are 1.2 nM and 58 nM and cortex levels are 0.8 nM and 31 nM for MnEt and MnHex (7 days sc 1 mg/kg bid). The ratios MnHex/MnEt=48 for hippocampus and MnHex/MnEt=39 for cortex further reflect the critical role of lipophilicity on the distribution within the brain. Hippocampus distribution is highly relevant due to its critical role in brain neurogenesis and neurocognition. Taken together, these data demonstrate the profound impact of lipophilicity and pentacationic charge on Mn porphyrin biodistribution and oral availability, as well as the advantage of lipophilic MnHex for treating CNS-related diseases and brain tumors. |
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