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-PyP5+ (AEOL10113, FBC-007) and MnTnHex-2-PyP5+ 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 normalO2•− 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-PyP5+ is approximately 4 orders of magnitude more lipophilic than MnTE-2-PyP5+, 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 24 h after single-dose drug administration. The porphyrins were administered intravenously (iv), intraperitoneally (ip), and via oral gavage at the following doses: 10 mg/kg MnTE-2-PyP5+ and 0.5 or 2 mg/kg MnTnHex-2-PyP5+. Drug levels in plasma and various organs (liver, kidney, spleen, heart, lung, brain) were determined and PK parameters calculated (Cmax, C24 h, 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-PyP5+ and 21% for MnTnHex-2-PyP5+. Despite the fivefold lower dose administered, the AUC values for liver, heart, and spleen are higher for MnTnHex-2-PyP5+ than for MnTE-2-PyP5+ (and comparable for other organs), clearly demonstrating the better tissue penetration and tissue retention of the more lipophilic MnTnHex-2-PyP5+.

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…The LCMS/MS technique was employed to analyze MnP levels in plasma, organs, tumors, and subcellular fragments (288,299). Figure 18 compares the key properties that affect the therapeutic potential of these MnPs.…”

“…18) (288, 289). For the purpose of comparison, we averaged their organ oral availability (expressed as AUC oral /AUC ip , where AUC ip /AUC iv is 83-84% for both compounds) (288). The ratio of AUC oral /AUC ip values for several major organs for MnTnHex-2-PyP 5 + and MnTE-2-PyP 5 + was calculated to be (33%)/(13%) = 2.2.…”

“…MnP levels were measured in brain (289) and in heart mitochondria and cytosol at 6 h after the last injection (250,254). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars (288). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars mouse heart mitochondria (1.4), brain (2.2), and all organs (2.2) strengthen the conclusion on the large impact of lipophilicity on their biodistribution.…”

“…Thus, we embarked on a PK journey. HPLC/fluorescence and later LCMS/MS methods were developed for each individual compound (140,177,238,250,252,254,288), which supported the comprehensive biodistribution studies. We have also expanded our synthetic efforts to increase porphyrin bioavailability.…”

Electrochemistry of redox-active Mn porphyrin-based SOD mimic MnTnBuOE-2-PyP5+ - Study of Redox Species Involved in ROS/RNS Scavenging

“…Comprehensive studies on bioavailability of these compounds have been performed recently as well [17][18][19], in order to gain further insight into the biodistribution of MnPs, but also provide guidelines for proper dosing regimens. After assessing preliminary efficacy and toxicity data, the porphyrins were administered to mice intraperitoneally (ip) or intravenously (iv) at following doses: 10 mg/kg of MnTE-2-PyP 5+ (ip) and 2 mg/kg of MnTnBuOE-2-PyP 5+ (iv).…”