Effect of iron overload on the metabolism and urinary recovery of 3-hydroxypyridin-4-one chelating agents in the rat.

Three orally active iron chelating agents from the 3-hydroxypyridin-4-one series of compounds were administered by gavage to both normal and iron-overloaded (500 mg Fe/kg) rats at a dose of 450 mumol/kg to investigate the effect of iron loading on metabolism and urinary recovery. Compounds selected for investigation were either poorly metabolized [1-(2'-hydroxyethyl) derivative, CP102] or predominantly biotransformed by either phase I [1,2-diethyl derivative, CP94] or phase II (1,2-dimethyl derivative, CP20) metabolic pathways. Unchanged drug and metabolite(s) recovered in urine were determined by HPLC and iron levels by atomic absorption spectrometry. Significant differences in recovery of unchanged drug were seen for both CP20 (L1) and CP94 between normal and iron-overloaded animals. In contrast, no such difference was seen for the poorly metabolized compound, CP102. For CP20 (L1), the proportion of unchanged drug excreted in the urine increased from 36.2 +/- 9.9% in normal animals to 78.7 +/- 8.1% (p < or = 0.02) in iron-loaded animals and 20.1 +/- 4.5% to 39.9 +/- 8.6% for CP94 (p < or = 0.05). A significant decrease in metabolite recovery of CP20 (L1) was seen with the 3-O-glucuronide conjugate decreasing from 38.2 +/- 8.8% in normal animals to 2.5 +/- 2.0% in the iron-overloaded group. The decrease of the 2-(1'-hydroxyethyl) metabolite of CP94 from 41.4 +/- 6.6% to 29.4 +/- 4.6% in the iron-loaded animals was, however, not statistically significant. Total dose recovered in the urine between normal and iron-overloaded animals was only significant for CP94 (p < or = 0.05).