Objective: Ibuprofen is the most commonly used drug for pharmacological closure of a patent ductus arteriosus (PDA) in premature infants. Ibuprofen is strongly bound to plasma albumin and could interfere with the binding of bilirubin to albumin and cause bilirubin toxicity. Most clinical studies have not shown increased concentrations of unbound bilirubin in plasma from infants treated with ibuprofen. This could be due to in-vivo equilibrium between different compartments and in-vitro studies have not been equally conclusive.

Methods: Plasma samples were obtained from jaundiced newborn infants and pooled to a bilirubin concentration of 176 μmol/l. Total bilirubin and unbound bilirubin were measured in vitro with the peroxidase method (UB-Analyser UA-1, Arrows Co Ltd, Osaka, Japan) after the addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 100 to 600 μg/ml. Bilirubin concentrations were varied from 176 to 708 μmol/l by adding bilirubin to plasma samples.

Results: Ibuprofen caused a linear increase in unbound bilirubin up to +59% at a concentration of 600 μmol/l, compared with an increase of 87.3% by sulfisoxazole (350 μg/ml). A double reciprocal plot of bound bilirubin versus unbound bilirubin at bilirubin concentrations ranging from 176 to 708 μmol/l showed a competitive displacement of bilirubin by ibuprofen.

Conclusions: The data indicate that ibuprofen is a strong competitive displacer of bilirubin in vitro. Until further clinical studies are performed, ibuprofen should be used with caution to treat PDA in newborn infants with a significant jaundice.