Kim Annink

207 Pharmacokinetics of allopurinol in the ALBINO trial described that morphine clearance in infants with HIE was about 21% lower during therapeutic hypothermia, which was both dependent on hepatic and renal clearance (38). The clearance of its metabolite was 15% lower in the hypothermia treated infants, which mainly depended on the renal clearance. So both the liver and kidneys seemed to have reduced clearing capacities in the hypothermia group, which has been confirmed by others (28,36,38). The AUC for oxypurinol depends on the metabolization of allopurinol into oxypurinol and renal clearance which can both be influenced by therapeutic hypothermia and severe asphyxia. Allopurinol is almost completely metabolized by the cytosolic enzyme aldehyde oxidase into oxypurinol, which is present throughout the body, and in high concentrations in the liver. A lower formation of oxypurinol will result in a lower AUC. Oxypurinol is eliminated by the kidneys, so impaired renal clearance due to therapeutic hypothermia or renal failure can lead to a higher AUC for oxypurinol, and in a lesser extent also for allopurinol. Because of the sample size, we were not able to estimate the effect of therapeutic hypothermia and organ failure in our cohort. In the current study, the uric acid concentrations decreased over time. The normal range for uric acid in neonates is approximately between 10 and 40 mg/L. Some allopurinol treated infants still had higher uric acid concentration. The study of van Bel et al. showed that uric acid levels were elevated and decreased over time in both the allopurinol and control group, but in the allopurinol group the concentrations of uric acid were significantly lower at all time points (18). Though allopurinol and oxypurinol inhibit the conversion of hypoxanthine into uric acid, it does not improve excretion of uric acid via the kidneys, which might explain the relatively high concentrations. There was one specific outlier in our cohort, with a significant lower AUC for oxypurinol, and - to a lesser extent - for allopurinol. The metabolic ratio (allopurinol/ oxypurinol ratio) was lower after the first and second dose, however, we should be cautious since oxypurinol has a long elimination half-life. We suggest that this outlier is most likely explained by a dosing error such as leakage during perfusion or a discrepancy between the prescribed and administered first dose, with a correct second dose. Although an additional poor metabolizer status for aldehyde oxidase cannot be excluded. Beedham et al. described that polymorphisms in the gene hAOX1, can lead to either poor and fast metabolizer variants (39). Unfortunately, 9