Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia

Abstract

The anticancer agent 3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase's small subunits, M2 and M2b (p53R2). Unfortunately, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe(2+)) in hemoglobin. This creates Fe(3+) methemoglobin that does not deliver oxygen. Fe(2+) in hemoglobin normally auto-oxidizes to inactive Fe(3+) methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen, ascorbate and, most importantly, intravenously administered methylene blue as a therapeutic antidote.

Figure 1. Recycling of methemoglobin to hemoglobin

Normal erythrocyte Hgb carries oxygen in a reversible association with reduced or ferrous iron (Fe²⁺). Oxygenated Fe²⁺ Hgb oxidizes to Fe³⁺ MetHgb and superoxide at a rate of approximately 3% per day. (A) In the presence of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), 3-AP interacts with the Fe²⁺ of Hgb in order to form 3-AP-Fe³⁺, which, in effect, creates MetHgb. (B) MetHgb may be reduced to Hgb by a combination of cytochrome b5 reductase and cytochrome b5. (C) The MetHgb antidote, methylene blue, can also facilitate this reaction. Hgb: Hemoglobin; MetHgb: Methemoglobin.

Figure 2. 3-aminopyridine-2-carboxaldehyde thiosemicarbazone pharmacokinetics and methemoglobin pharmacodynamics

Plasma concentration of 3-AP was determined in ten women with cervical cancer undergoing 3-AP radiochemotherapy. (A) Peak 3-AP concentration was observed at the end of a 2-h infusion. (B) Peak methemoglobin levels were detected 2 h after discontinuation of 3-AP infusion. (A & B) A vertical bar denotes the 4-h time point after the start of infusion. 3-AP: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; MetHgb: Methemoglobin.