Bilirubin Unbound: Deja Vu All Over Again?

During the last century it was widely accepted that when drugs that bind avidly to albumin are displaced from the protein, the resulting increase in the concentration of unbound (free) drug would cause increased biological activity and toxicity.1 Supporting examples were thought to be the severe hypoglycemia that is observed in diabetic patients taking sulfonamides in addition to tolbutamide and the potentiation of the effects of warfarin by phenylbutazone in human volunteers. In both instances, the ancillary drug displaces the therapeutic drug from albumin in vitro. Nowadays, it is recognized that factors other than increased unbound drug were responsible for the observed clinical phenomena, and changes in plasma concentrations of free drug are thought to have little clinical relevance except in unusual situations.1–3 The obvious analogy between bilirubin, with its strong affinity for serum albumin, and highly protein-bound drugs (along with the sulfisoxazole tragedy4) led to suggestions long ago that the concentration of unbound bilirubin in the circulation of jaundiced neonates might be a better predictor of the risk of bilirubin encephalopathy than the total concentration of bilirubin. However, accurate measurement of this minute fraction in clinical samples proved difficult and, according to one authority, beyond the capabilities of instrumentation then available.5 Nevertheless, the notion that unbound-bilirubin measurements might be clinically useful and more discriminating than total bilirubin measurements for identifying infants at most risk of kernicterus has persisted. In this issue of Pediatrics , Wennberg et al6 summarize the reasons for this and re-present the case for investigating whether measurements of unbound bilirubin, based on a peroxidase assay, really are worthwhile in the management of neonatal jaundice. They review the experimental and clinical evidence that the apparent unbound-bilirubin concentration is a better predictor of brain uptake and toxicity of bilirubin than the … Address correspondence to Antony F. McDonagh, PhD, Room S-357, Box 0538, University of California, San Francisco, CA 94143. E-mail: tony.mcdonagh{at}ucsf.edu; or M. Jeffrey Maisels, MB, BCh, Department of Pediatrics, William Beaumont Hospital, 3535 W 13 Mile Rd, 709, Royal Oak, MI 48073. E-mail: jmaisels{at}beaumont.edu