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 hydroxypyridinone (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 contrasting metabolism of this compound in the two species. CP94 was highly effective at mobilizing liver iron in rats but showed toxicity at higher doses, whereas in the guinea-pig the compound lacked toxicity but was ineffective at mobilizing liver iron. These differences can be explained by the contrasting metabolism of the drug between the two species. In rats, at the top dose of 300 mg/kg intragastrically, all animals died before the end of the study, with no deaths or weight loss at lower doses. At 100 mg/kg, rat liver non-haem iron concentrations were reduced by 53% and 44% in females and males respectively (P < 0.001). At this dose, adrenal medullary cell vacuolation, increased mammary secretory 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 decreased by 50% and 34% in females and males respectively (P < 0.02). In female rats this was associated with increased mammary secretory activity. 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 ferritin by 71% (P < 0.001). Ovarian and mammary changes were not influenced 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 liver iron was seen and no systematic dose related histological, biochemical or haematological effects were observed. Whereas in guinea-pigs 99% of urinary recovery following an oral dose of CP94 (100 mg/kg) was as the inactive glucuronide metabolite, in the rat only 23% of the dose was excreted in the urine as the glucuronide with remainder as the free drug or an iron binding metabolite. The lack of both efficacy and toxicity in the guinea-pig may therefore be explained by the rapid inactivation of CP94 by glucuronidation. This metabolism of CP94 in the guinea-pig is closer to humans than the rat, suggesting that both the efficacy and toxicity of this compound in humans may also be limited by glucuronidation.
Porter
J B
JB
Department of Haematology, University College London.
Abeysinghe
R D
RD
Hoyes
K P
KP
Barra
C
C
Huehns
E R
ER
Brooks
P N
PN
Blackwell
M P
MP
Araneta
M
M
Brittenham
G
G
Singh
S
S
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005293:Ferritins / Q000097:blood; D006168:Guinea Pigs; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D011728:Pyridones / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D007502:Iron Chelating Agents; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D005293:Ferritins; D007501:Iron