Effect of ibuprofen on bilirubin–albumin binding in vitro at concentrations observed during treatment of patent ductus arteriosus

Abstract 

Background

In vitro studies have shown that ibuprofen (IBU) may interfere with bilirubin–albumin binding at concentrations of 100µg/mL and above.

Objectives

The present study evaluates the in vitro bilirubin displacement over the range of IBU plasma concentrations observed in vivo during curative treatment of patent ductus arteriosus in preterm infants.

Methods

Considering that individual plasma concentrations obtained during the clinical development of IBU in preterm infants were ranging between 10 and 70µg/mL and exceptionally above 100µg/mL, we used the modified peroxidase method to determine total and unbound bilirubin concentrations without IBU and with IBU over this specific concentration range.

Results

Total bilirubin and albumin concentrations were respectively 6.6mg/dL and 2.87g/dL in pooled newborn plasma. No displacement of bilirubin from its albumin binding sites by IBU was observed over a range of concentrations from 10 to 100µg/mL. Only a concentration of 200µg/mL significantly increased the unbound bilirubin by 1.5-fold (p=0.0008).

Conclusions

This in vitro study confirms displacement of bilirubin by a high IBU concentration of 200µg/mL, however it retrieves no significant displacement over a range of concentrations up to and including 100µg/mL, i.e. within the range of in vivo concentrations at the recommended dose regimen.

Abbreviations: d_f, unbound drug concentration, K_D, equilibrium association drug-albumin binding constant, HsPDA, hemodynamically significant patent ductus arteriosus, B:A ratio, bilirubin/albumin molar ratio, UB, unbound bilirubin, TB, total bilirubin, IBU, ibuprofen

Keywords: Ibuprofen, Patent ductus arteriosus, Preterm infants, Unbound bilirubin, Kernicterus, Neonate