Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.

ABSTRACT

BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24-32 weeks' gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration-time curves (AUC0-500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.