CONTRASTING INTERSPECIES EFFICACY AND TOXICOLOGY OF 1,2-DIETHYL-3-HYDROXYPYRIDIN-4-ONE, CP94, RELATES TO DIFFERING METABOLISM OF THE IRON-CHELATING SITE

In order to define a predictive animal model for the effects of hydrox ypyridinone (HPO) iron chelators in humans, we have compared the 28 d oral efficacy and toxicology of the HPO, 1,2-diethyl-3-hydroxypyridin- 4-one (CP94) in rats and guinea-pigs and related the results to the co ntrasting metabolism of this compound in the two species. CP94 was hig hly effective at mobilizing liver iron in rats but showed toxicity at higher doses, whereas in the guinea-pig the compound lacked toxicity b ut was ineffective at mobilizing liver iron. These differences can be explained by the contrasting metabolism of the drug between the two sp ecies. In rats, at the top dose of 300 mg/kg intragastrically, all ani mals died before the end of the study, with no deaths or weight loss a t lower doses. At 100 mg/kg, rat liver non-haem iron concentrations we re reduced by 53% and 44% in females and males respectively (P<0.001). At this dose, adrenal medullary cell vacuolation, increased mammary s ecretory activity, vacuolation of corpora luteal cells and single cell hepatocyte necrosis were seen. There were no reductions in the white cell count. At 50 mg/kg rat liver non-haem iron concentrations were de creased by 50% and 34% in females and males respectively (P<0.02). In female rats this was associated with increased mammary secretory activ ity. In iron-overloaded rats given 100 mg/kg by gavage for 28 d, liver non-haem iron concentration was reduced by 39% (P<0.01) and serum fer ritin by 71% (P<0.001). Ovarian and mammary changes were not influence d by iron loading. In guinea-pigs, CP94 was evaluated at 50 mg/kg, 100 mg/kg or 200 mg/kg by oral insufflation for 28 d. No reduction in liv er iron was seen and no systematic dose related histological, biochemi cal or haematological effects were observed. Whereas in guinea-pigs 99 % of urinary recovery following an oral dose of CP94 (100 mg/kg) was a s the inactive glucuronide metabolite, in the rat only 23% of the dose was excreted in the urine as the glucuronide with remainder as the fr ee drug or an iron binding metabolite. The lack of both efficacy and t oxicity in the guinea-pig may therefore be explained by the rapid inac tivation of CP94 by glucuronidation. This metabolism of CP94 in the gu inea-pig is closer to humans than the rat, suggesting that both the ef ficacy and toxicity of this compound in humans may also be limited by glucuronidation.