Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

Journal Article · Sat Dec 01 04:00:00 EST 1990 · Blood (Journal of Hematology); (USA)

OSTI ID:6213587

Porter, J B; Morgan, J; Hoyes, K P; Burke, L C; Huehns, E R; Hider, R C ^[1]

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1. Univ. College and Middlesex School of Medicine, London (England)

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).

• OSTI ID: 6213587
• Journal Information: Blood (Journal of Hematology); (USA), Journal Name: Blood (Journal of Hematology); (USA) Vol. 76:11; ISSN 0006-4971; ISSN BLOOA
• Country of Publication: United States
• Language: English

Related Subjects

550501* -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
CHELATING AGENTS
CLEARANCE
COMPARATIVE EVALUATIONS
DAYS LIVING RADIOISOTOPES
DOSE-RESPONSE RELATIONSHIPS
EVEN-ODD NUCLEI
EXCRETION
FECES
INJECTION
INTAKE
INTERMEDIATE MASS NUCLEI
INTRAPERITONEAL INJECTION
IRON 59
IRON ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
MAMMALS
MATERIALS
METABOLISM
MICE
NUCLEI
ORAL ADMINISTRATION
RADIOISOTOPES
RODENTS
SOLUBILITY
STRUCTURE-ACTIVITY RELATIONSHIPS
TOXICITY
TRACER TECHNIQUES
VERTEBRATES
WASTES