Displacement of Bilirubin From Albumin by Ibuprofen In Vitro

Abstract

Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 M by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to ϩ54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 M showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia. (Pediatr Res 67: 614-618, 2010) T he significance of unconjugated hyperbilirubinemia is the potential for development of bilirubin neurotoxicity and kernicterus. Most healthy term infants with a total serum bilirubin (TB) concentration reaching 425 to 680 M will, however, escape with no significant damage when treated with phototherapy and/or exchange transfusion according to guidelines (1). However, 8 to 9% of the kernicterus cases occur at a TB concentration Ͻ425 M. Kernicterus has also been reported at TB concentrations Ͻ340 M (2,3). In premature infants, bilirubin toxicity has been observed at even lower TB concentrations (4,5). More recently, high peak TB has been associated with poor long-term prognosis and adverse neurodevelopmental outcome in extremely low birth weight infants (6,7).The binding site of bilirubin on the albumin molecule is still uncertain, but most likely bilirubin binds to albumin at one high affinity binding site in a 1:1 molar ratio (3,8 -10). Clinical and experimental data have also suggested different secondary binding sites. However, these secondary binding sites may not be of any physiologic importance (10). At equilibrium, ϳ0.005% of bilirubin will be unbound bilirubin (UB). The albumin-bilirubin complex has a high molecular weight and cannot cross capillary walls, whereas UB is available for tissue distribution and elimination (9,11). Bilirubin is not toxic while bound to albumin (BB), and it is thought that the concentration of UB is a better predictor of toxicity than TB. The distribution and elimination of UB causes a shift in the equilibrium, and more bilirubin is released from albumin. The concentration of UB is influenced by several factors like the concentration of TB (2), albumin, and the binding capacity of albumin (5). Of clinical importance is the fact that the bindi...

Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction

“…Ibuprofen, one of the drugs used for treating patent ductus arteriosus in preterm infants, is a potent bilirubin displacer and has been shown to increase UB concentrations in vitro [21,22]. However, recent in-vivo studies have shown that ibuprofen does not displace bilirubin and increase UB concentrations in preterms with mild to moderate hyperbilirubinemia [23,24].…”

Paracetamol to induce ductus arteriosus closure: is it valid?

“…In addition, there are contra-indications for ibuprofen or indomethacin administration. These include thrombocytopenia or intracranial haemorrhage (impaired platelet activity), renal failure (due to decreased renal perfusion), necrotising enterocolitis, coadministration of corticosteroids (risk of intestinal perforation) or hyperbilirubinemia (competitive binding to albumin) 1–4 10. Most of these contra-indications relate to the pharmacological effects of ibuprofen or indomethacin, that is, a concentration related reduction in prostaglandin synthesis through non-selective inhibition of the COX site of the prostaglandin H 2 synthetase (PGHS) enzyme (figure 1).…”

Contribution of Baicalin on the Plasma Protein Binding Displacement and CYP3A Activity Inhibition to the Pharmacokinetic Changes of Nifedipine in Rats In Vivo and In Vitro

“…We discovered that baicalin competitively displaces nifedipine from plasma protein binding sites as demonstrated by the change in slope of the double reciprocal plot (Figure 4C) obtained from the in vitro plasma protein binding experiment [44]. The C max values of baicalin in rats treated with baicalin (0.225, 0.45 g/kg) were 754.8 mg/L and 1,280.4 mg/L, respectively, and when the concentration of baicalin was increased above 250 mg/L, the unbound nifedipine significantly increased in the in vitro study (Figure 4C).…”