Abstract
PurposeManganese porphyrins are redox-active drugs and superoxide dismutase mimics, which have been shown to chemosensitize lymphoma, a cancer which frequently occurs in dogs. This study aimed to identify critical information regarding the pharmacokinetics and toxicity of Mn(III) meso-tetrakis (N-n-butoxyetylpyridium-2-yl) porphyrin, (MnTnBuOE-2-PyP5+, MnBuOE) in dogs as a prelude to a clinical trial in canine lymphoma patients.MethodsA single-dose pharmacokinetic (PK) study in normal dogs was performed to determine the plasma half-life (t1/2) of MnBuOE. A dose reduction study was performed to establish the maximum tolerated dose (MTD) of MnBuOE. The safety and PK of a multi-dosing protocol was assessed.ResultsPeak plasma drug concentration occurred 30 min post-injection. The t1/2 was defined as 7 h. MnBuOE induced an anaphylactic reaction and prolonged tachycardia. The MTD was defined as 0.25 mg/kg. The dogs were given MTD 3×/week for 2–3 weeks. The highest recorded tissue drug levels were in the lymph nodes (4–6 μM), followed by kidney and liver (2.5, 2.0 uM, respectively).ConclusionsWe obtained critical information regarding the PK and toxicity of MnBuOE in dogs. The acute drug reaction and tachycardia post-injection have not been described in other species and may be specific to canines. The high tissue drug levels in lymph nodes have not been previously reported. MnBuOE accumulation in lymph nodes has important implications for the utility of adjuvant MnBuOE to treat lymphoma. With MnBuOE lymph node accumulation, reduction in the dose and/or administration frequency could be possible, leading to reduced toxicity.
Highlights
Cancer therapy should operate with a wide therapeutic index whereby tumor cells are preferentially killed and normal tissues are protected
While the increase in oxidative stress contributes to tumor cell cytotoxicity, it can be damaging to normal tissues
Compartmental calculations including 0–48 h data were performed on the averaged PK profile for the purpose of obtaining PK parameters needed for the simulation of the multi-dose regimen
Summary
Cancer therapy should operate with a wide therapeutic index whereby tumor cells are preferentially killed and normal tissues are protected. The most common cancer treatments are toxic to both tumor and normal tissues and the therapeutic index is narrow. Increased oxidative stress has been observed after radiation therapy, several common chemotherapy agents, and even targeted agents [1,2,3,4]. MnBuOE is a superoxide dismutase (SOD) mimic, which has been shown to sensitize tumor cells to chemotherapy and radiotherapy while protecting normal tissue by modulating tissue reduction-oxidation (redox) status [5,6,7,8,9]. We have reviewed the structure–activity relationships and impact of these manganese porphyrin therapeutics on cellular redox-based signaling pathways [10]
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