The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome.
OBJECTIVE
The purpose of this investigation was to determine the pharmacokinetic disposition of intravenous allopurinol and its metabolite oxypurinol in neonates with the hypoplastic left heart syndrome (HLHS) and to evaluate the subsequent degree of xanthine oxidase inhibition using serum uric acid as a marker.


METHODS
Pharmacokinetic data were evaluated in 12 stable preoperative neonates with HLHS after a single intravenous allopurinol administration of 5 mg/kg or 10 mg/kg. Pharmacokinetic parameters were determined for elimination half-life, clearance, volume of distribution, and mean residence time. Xanthine oxidase inhibition, measured by serum uric acid reduction, was also measured.


RESULTS
Pharmacokinetic parameters revealed no statistically significant differences between a 5-mg/kg and 10-mg/kg dose of intravenous allopurinol on elimination half-life, clearance, volume of distribution, and mean residence time. Mean serum uric acid levels were significantly reduced from baseline by 39.99 and 42.94%, respectively, in the 5- and 10-mg/kg treatment groups.


CONCLUSIONS
The enzyme xanthine oxidase plays a key biochemical role in the generation of toxic oxygen-derived free radicals during ischemia-reperfusion conditions. Allopurinol and its active metabolite oxypurinol inhibit xanthine oxidase, and significantly reduce the conversion of hypoxanthine to xanthine and xanthine to uric acid. Cell injury may be caused by toxic oxygen free radicals produced by ischemia-reperfusion injury such as could occur during the repair of HLHS under hypothermic total circulatory arrest. We hypothesize that allopurinol may provide protection from cellular injury in this clinical context.
Division of Neurology, Children's Hospital of Philadelphia.
S P
SP
McGaurn
L E
LE
Davis
M M
MM
Krawczeniuk
J D
JD
Murphy
M L
ML
Jacobs
W I
WI
Norwood
R R
RR
Clancy
D000493:Allopurinol / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000097:blood* / Q000188:drug therapy*; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D010117:Oxypurinol / Q000097:blood; D013997:Time Factors; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000187:drug effects
D007042:Hypoxanthines; D014527:Uric Acid; D019271:Hypoxanthine; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol