Nephrol Dial Transplant Vol. 19 No. 10 © ERA-EDTA 2004; all rights reserved
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Coyne proposes that peak plasma levels achieved after i.v. injection of ferric gluconate are half those of other i.v. iron agents, that the effect of labile iron in i.v. iron agents is attenuated by a short plasma half-life of ferric gluconate, that ferric gluconate can be infused more rapidly than iron sucrose, that high-dose infusions may not be safe for any i.v. iron agent, and that in vitro results have no bearing on the safety of i.v. iron administration in patients. Each point warrants discussion.I.v. iron agents are colloids which, when injected intravenously, are distributed in the plasma space, so that the calculated initial volume of distribution roughly approximates plasma volume. This is true for iron sucrose [1] and iron dextran [2]. The reported finding that ferric gluconate achieves a peak plasma concentration only half of that expected prompts the conclusion that the agent is distributed in a volume equal to twice the plasma volume [3]. The resulting conclusion that 50% of the iron in ferric gluconate immediately dissociates from the compound and exits the intravascular space seems quantitatively implausible (our estimates would suggest 5–7%). Qualitatively, however, the pharmacokinetics of ferric gluconate support our finding that the labile iron fraction in this agent is not inconsiderable and may be clinically important early after i.v. administration.
Iron donation from i.v. iron agents to transferrin takes place immediately [4]. Prolonged exposure of agent to plasma leads to greater degrees of iron donation [5]. Thus, a short plasma half-life would not affect early iron donation. Rapid cellular uptake may limit late iron donation in plasma only to augment the intracellular manifestations of labile iron to which Coyne alludes.
Reactions consistent with a labile iron pathogenesis afflict 30% of patients administered 500 mg ferric gluconate i.v. over 5 h and 10% of patients given 250 mg i.v. over 3–4 h [6]. Administration of 200 mg of iron sucrose i.v. over 5 min is well tolerated [7], as is administration of 200 mg i.v. over 2 min [8]. Iron dextran has been given as aggressively as 250–500 mg over 5–10 min without evidence of labile iron reaction [9,10]. Our results showing the relative bioactivity of i.v. iron agents (ferric gluconate > iron sucrose > iron dextran) suggest that labile iron may play a role in limiting the maximum tolerated dose and rate of infusion (ferric gluconate < iron sucrose < iron dextran). The observation that in vitro results may lack in vivo correlates does not necessarily diminish their significance. In vitro i.v. iron studies that are comparative and carefully executed [5,11–13] identify potential new areas for investigation in patients, confirm that manifestations of labile iron follow the relative sequence ferric gluconate > iron sucrose > iron dextran, and lend appropriate caution to the administration of i.v. iron agents.
Conflict of interest statement. I am a consultant and member of the speakers board for American Regent Inc.
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