Effect of Phenobarbitone on Plasma [14C]Bilirubin Clearance in Patients with Unconjugated Hyperbilirubinaemia

Abstract

1. The clearance of a tracer dose of [14C]bilirubin from the plasma was studied in patients with Gilbert's syndrome, congenital non-haemolytic jaundice, haemolytic jaundice and in normal subjects. Clearance was significantly impaired in the patients with Gilbert's syndrome and in those with congenital non-haemolytic jaundice when compared with the normal subjects, and was normal in the patient with haemolytic jaundice. 2. Treatment for 2 weeks with phenobarbitone (180 mg/day) lowered the plasma bilirubin concentration and improved all indices of plasma clearance of the isotope in patients with Gilbert's syndrome, so that they became indistinguishable from those of normal subjects. The improvement in plasma [14C]bilirubin clearance in these patients was associated with modest increases in hepatic bilirubin glucuronyl transferase in some subjects. 3. Phenobarbitone treatment improved plasma bilirubin concentrations and plasma [14C]bilirubin clearance in patients with congenital non-haemolytic jaundice, so that they resembled those seen in patients with untreated Gilbert's syndrome. Despite this improvement hepatic bilirubin glucuronyl transferase activity remained undetectable. 4. These results are compatible with the hypothesis that Gilbert's syndrome is a manifestation of a relative deficiency of hepatic bilirubin glucuronyl transferase, and differs from congenital non-haemolytic jaundice only in severity.

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

“…Induction of bilirubin UGT is widely accepted as the mechanism by which phenobarbital therapy lowers serum bilirubin levels in individuals with unconjugated hyperbilirubinemia. 12,15,16,29 Fur- thermore, Sutherland et al 17 reported markedly higher UGT1A1 mRNA levels in 2 patients exposed to phenobarbital or the phenobarbital-like inducer, phenytoin, and in this study, the 3 donor samples with the highest levels of UGT1A1 protein were from individuals with a documented history of phenytoin therapy at the time of death. Yet our study revealed surprisingly weak hepatocyte UGT1A1-inducing effects of phenobarbital.…”

“…14 Although bilirubin excretion is clearly increased in humans by phenobarbital, attempts to demonstrate that the effect is actually the result of elevated bilirubin UGT activity (i.e., UGT1A1) in human liver has had varied outcomes. 15,16 Following the identification of UGT1A1 as the major bilirubin glucuronidating UGT, 2,3 only 2 studies have specifically addressed the inducibility of hepatic UGT1A1 in primate species using UGT1A1-specific molecular probes. No effect of phenobarbital was observed on the UGT1A1 mRNA level in liver samples from phenobarbital-exposed monkeys.…”

Bilirubin kinetics in intact rats and isolated perfused liver. Evidence for hepatic deconjugation of bilirubin glucuronides.

“…In addition, more complex models have been proposed to accommodate the bilirubin fractions derived from turnover ofhepatic heme and hemoproteins (12)(13)(14). These models have been used to interpret data derived from plasma radiobilirubin disappearance studies in various human disorders associated with unconjugated hyperbilirubinemia (13,(15)(16)(17)(18)(19).…”

Jaundice: a basic review

“…[10][11][12][13][14] Conjugated bilirubin is excreted into the bile. The bile is then passed to the duodenum via biliary system.…”