title: Pharmacokinetics of representative 3-hydroxypyridin-4-ones in rabbits: CP20 and CP94.
abstract: Selected 3-hydroxypyridin-4-ones (HPs) are under clinical investigation as iron chelators. Representative HPs have been shown to be potential aluminum chelators by use of in vitro test systems. This study was conducted to determine systemic availability of representative HPs in rabbits prior to studies of their oral efficacy as aluminum chelators. Each of 12 rabbits was administered 0.45 mmol/kg 1,2-dimethyl- (CP20; L1) and of 1,2-diethyl-3-hydroxypyridin-4-one (CP94; EL1NEt) by gastric lavage and by injection into a lateral ear vein. Each rabbit received both compounds via both routes with at least 7 days between doses. Blood samples (1.5 ml) were collected up to 24 hr after dosing. The HPs were extracted, then analyzed by HPLC with a column packed with graphitized carbon. The mean (+/- SD) systemic clearance, steady-state volume of distribution, mean residence time, mean oral absorption time, and systemic availability for CP20 and CP94 were 0.8 +/- 0.3 and 2.1 +/- 1.4 liter/hr/kg; 1.2 +/- 0.5 and 1.2 +/- 0.5 liter/kg; 1.7 +/- 0.7 and 0.7 +/- 0.3 hr; 0.9 +/- 1.6 and 0.6 +/- 0.5 hr; and 72 +/- 20 and 57 +/- 27%, respectively. Rabbits demonstrated fairly good absorption and rapid elimination of 1,2-dimethyl- and 1,2-diethyl-3-hydroxypyridin-4-one.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington.
authors.forename: A M
authors.initials: AM
authors.lastname: Fredenburg
authors.forename: P J
authors.initials: PJ
authors.lastname: Wedlund
authors.forename: T L
authors.initials: TL
authors.lastname: Skinner
authors.forename: L A
authors.initials: LA
authors.lastname: Damani
authors.forename: R C
authors.initials: RC
authors.lastname: Hider
authors.forename: R A
authors.initials: RA
authors.lastname: Yokel
mesh_terms: D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D000077543:Deferiprone; D007408:Intestinal Absorption; D008297:Male; D011728:Pyridones / Q000493:pharmacokinetics*; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet
chemical_list: D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D000077543:Deferiprone