title: Metabolic and pharmacokinetic evaluation of a novel 3-hydroxypyridinone iron chelator, CP502, in the rat.
abstract: A recently synthesized 3-hydroxypyridinone derivative with an amido function at the 2-position, CP502 (1,6-dimethyl-3-hydroxy-4-(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride), exhibited high in vitro iron chelating potency (pFe3+ =21.7). It was targeted as a new iron-chelating candidate for further development in early pre-clinical testing. To evaluate its pharmacokinetics, including oral bioavailability, metabolic and disappearance profiles, studies were conducted in Sprague Dawley male rats. A single 150 mg/kg intravenous and oral dose was given to male Sprague Dawley rats (N=6, B.Wt. 250g). The rats were placed in metabolic cages and fasted overnight before the dosing. Venous blood samples (200 microL per withdrawal) were collected at defined time points before (blank) and up to 28 h post administration. Urine and feces were collected before dosing (blank) and in 24 h intervals up to 72 h post administration. Plasma CP502 concentration versus time profiles were consistent with two-compartment distribution, and the oral bioavailability approached 100%. Total clearance and mean residence time (i.v.) were 1.02 L/kg/h and 1.10 h, respectively. Simultaneous computer fitting yielded V1 and Vss estimates of 0.96 L/kg and 1.74 L/kg, respectively. CP502 was mainly excreted unchanged via urine (45.29+/-9.40 % of total dose) or as glucuronide (6.46+/-1.22% of total dose). High iron chelation potential and favorable pharmacokinetic and metabolic profiles indicate that CP502 is a promising candidate for further development.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Novakovic
authors.forename: Angelo
authors.initials: A
authors.lastname: Tesoro
authors.forename: Jake J
authors.initials: JJ
authors.lastname: Thiessen
authors.forename: Michael
authors.initials: M
authors.lastname: Spino
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007502:Iron Chelating Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D011728:Pyridones / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C487538:1,6-dimethyl-3-hydroxy-4-(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride; D007502:Iron Chelating Agents; D011728:Pyridones
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