Contrasting interspecies efficacy and toxicology of 1, 2 -diethy 1–3 -hydroxypyridin-4-one, CP9 4, relates to differing metabolism of the iron chelating site

摘要: Summary. In order to define a predictive animal model for the effects of hydroxypyridinone (HPO) iron chelators in humans, we have compared 28 d oral efficacy and toxicology HPO, 1,2-diethyI-3–hydroxypyridin-4–one (CP94) rats guinea-pigs related results contrasting metabolism this compound two species. CP94 was highly effective at mobilizing liver but showed toxicity higher doses, whereas guinea-pig lacked ineffective iron. These differences can be explained by drug between rats, top dose 300 mg/kg intragastrically, all animals died before end study, with no deaths or weight loss lower doses. At 100 mg/kg, rat non-haem concentrations were reduced 53% 44% females males respectively (P<0.001). dose, adrenal medullary cell vacuolation, increased mammary secretory activity, vacuolation corpora luteal cells single hepatocyte necrosis seen. There reductions white count. 50 decreased 50% 34% (P<0.02). female associated activity. iron-overloaded given gavage d, concentration 39% (P<0.01) serum ferritin 71% Ovarian changes not influenced loading. guinea-pigs, evaluated 200 insufflation d. No reduction seen systematic histological, biochemical haematological observed. Whereas 99% urinary recovery following an (100 mg/kg) as inactive glucuronide metabolite, only 23% excreted urine remainder free binding metabolite. The lack both may therefore rapid inactivation glucuronidation. This is closer humans than rat, suggesting that also limited