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Displacement effect of valproate on bilirubin-albumin binding in human plasma
1School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Insights
Valproate (VPA) can displace bilirubin from albumin binding in newborns. This drug interaction may increase the risk of brain damage in jaundiced infants, warranting cautious use of VPA in neonates.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Biochemistry
Background:
- Unconjugated hyperbilirubinemia in newborns poses a risk for brain damage.
- Drugs displacing bilirubin from plasma albumin binding can exacerbate this risk.
- Valproate (VPA) is a commonly used anticonvulsant with potential protein-binding interactions.
Purpose of the Study:
- To investigate the bilirubin displacement effect of valproate (VPA) on human serum albumin (HSA) and plasma protein binding.
- To determine the clinical relevance of VPA's displacement potential in neonatal hyperbilirubinemia.
Main Methods:
- Preparation of bilirubin-HSA and bilirubin-plasma solutions with varying VPA concentrations.
- Measurement of free bilirubin using the enzyme oxidation method.
- Calculation of binding constants (KD) and displacement factors.
Main Results:
- Valproate (VPA) demonstrated a significant displacement effect on bilirubin from albumin and plasma protein binding.
- The binding constants (KD) for VPA were 11.6 L/mmol for HSA and 9.0 L/mmol for plasma.
- Maximal displacement factors ranged from 1.5 to 4.7 at clinically relevant VPA concentrations.
Conclusions:
- Valproate (VPA) can displace bilirubin from protein binding in vitro, suggesting a potential risk in vivo.
- Clinicians should exercise caution when administering VPA to neonates with jaundice and unconjugated hyperbilirubinemia.
- Further studies may be needed to fully elucidate the clinical implications of VPA-bilirubin interaction in neonates.
Abstract:
Drugs that can displace bilirubin from plasma albumin binding may cause various late manifestations of brain damage if given to newborns with unconjugated hyperbilirubinemia. The purpose of this study was to examine the displacement effect of valproate (VPA) on bilirubin-albumin binding in human serum albumin (HSA) and human plasma. Bilirubin-HSA solution and bilirubin-plasma solution containing no or serial concentrations of VPA were prepared, and free bilirubin in these solutions was measured by the enzyme oxidation method. VPA displaced bilirubin from bound bilirubin-albumin. The binding constant (KD) of VPA to the high affinity bilirubin-binding site of HSA and plasma protein were 11.6 L/mmol and 9.0 L/mmol respectively. The displacement effect may occur at the clinical concentration range of VPA, with a maximal displacing factor of 1.5 to 4.7. These results suggest that the clinician should use VPA in jaundiced neonates with caution.