Pharmacokinetics of aluminum 3-hydroxypyridin-4-one complexes: implications for aluminum redistribution subsequent to chelation therapy.
The pharmacokinetics of selected aluminum-hydroxypyridinone (Al-HP complexes were determined in rats to better understand the relationship between their disposition and elimination parameters and the safety of HPs in the chelation therapy of Al intoxication. Five complexes were administered as i.v. bolus doses of Al-HP (0.25 mmol/kg Al-0.75 mmol/kg HP). The Al-HP steady state volumes of distribution ranged from 220 to 871 ml/kg, suggesting that each complex distributed out of the vascular compartment (which should have been approximately 65 ml/kg). Systemic clearances ranged from 189 to 906 ml/h per kg. Elimination half-lives (t1/2) and mean residence times ranged from 0.36 to 0.84 and 0.52 to 1.20 h, respectively. The Al-CP20 complex had a short t1/2 and a midrange volume of distribution. It demonstrated no apparent toxicity, whereas myoclonic seizures were observed after Al-CP22, Al-CP24 and Al-CP94 administration. The most appropriate choice for Al chelation among the HPs tested may be CP20. Characterization of the distribution and elimination of Al-HP complexes improves the understanding of potential toxicity that may be associated with HP therapy of Al intoxication.
Allen
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College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082.
Orvig
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Yokel
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D000535:Aluminum / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D002614:Chelating Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D008954:Models, Biological; D011728:Pyridones / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis
D002614:Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D000535:Aluminum