Iron mobilizing ability of 1,2-diethyl-3-hydroxypyridin-4-one(CP94) in iron-overloaded rats

Abstract

An iron mobilizing ability of a new orally active iron chelator, 1,2diethyl-3-hydroxypyridin-4-one (CP94) was studied in iron-overloaded rats. The study was performed in both normal and iron-overloaded rats, having the right jugular vein pre-cannulated with a catether 24-hr before the experiment. The catheter was used for drug administration and blood sampling. Iron overloaded rats were prepared by giving thirty two milligrams of iron (as iron dextran) intraperitoneally to normal rats (2 times per week) over a period of one month. This model was able to build up 8-fold increase of liver iron while the level of serum iron was not changed. Serum TBARs, an indicator of lipid peroxidation, was significantly elevated in iron-overloaded rats. This study provided an animal model for ascessing the initial iron mobiltizing activity of the chelator once it get into the cirrculating blood. A single iv-dose of 100 mg/kg CP94 was given directly into the right atrium via the catheter in a concious rat. The result showed that plasma profile of CP94 in iron-overloaded rats was not different from that of normal rats. One hour after the administration of CP94, serum iron was significantly elevated in the iron overloaded rats while minimal change was observed in normal controls. This evidence indicated that CP94 has a potent iron mobilizing ability once it appeared in the plasma without having the CP94 penetrated into the iron deposited pool. The indifferent of plasma levels and pharmacokinetic parameters of CP94 in both iron-overloaded and normal rats supported this contention. The appearance of higher levels of serum iron when serum CP94 had almost disappeared from the circulating blood suggesting that iron might form complexes with either active metabolites of CP94 eg., hydroxylated metabolite or other plasma factors. Increased urinary excretion of iron at the first 2-hr coincided with peak plasma level of Fe indicating that CP94 was responsible for attracting iron from the deposited pool to the central (blood) compartment and then excreted into the urine. With the fall of serum TBARs as early as 1 hr after giving the CP94, it was likely that CP94 might have an antioxidant activity in addition to its iron chelating property.