Alteration of drug metabolism in Gilbert's syndrome.
Open Access
- 1 August 1976
- Vol. 17 (8), 581-587
- https://doi.org/10.1136/gut.17.8.581
Abstract
The pathophysiology of Gilbert's syndrome was studied by investigating the metabolism of the drug tolbutamide, which is metabolised by the liver but does not undergo glucuronidation. Using rat liver cell supernatant, tolbutamide was shown to bind to the hepatic cytoplasmic Y protein in a manner similar to other organic anions, but not to Z protein. In 31 patients with Gilbert's syndrome the plasma disappearance (plasma half-life, mean +/- SD: 628+/-84 min) and metabolic clearance (7-9+/-1-8 ml/min) were significantly (P less than 0-0005) altered compared with the 13 controls (mean half-life 393+/-26 and mean clearance 13-4+/-1-5). The eight patients with hyperbilirubinaemia due to haemolytic disease showed no difference from the normal control subjects. In three patients with Gilbert's syndrome the cumulative urinary excretion of tolbutamide metabolites, 24 hours after the administration of the drug, was 30% lower than in the controls. In the five patients with Gilbert's syndrome, phenobarbital administration (100 mg/day) produced a significant increase in clearance of the drug from 8-8+/-0-8 to 13-4+/-1-9 ml/min; this was paralleled by a fall in serum bilirubin concentration. The plasma half-life of tolbutamide was similar in Gunn rats and Wistar rats. The results suggest that the metabolic defect(s) of Gilbert's syndrome affects compounds other than bilirubin and that defective uptake is probably the major factor.Keywords
This publication has 20 references indexed in Scilit:
- Liver ultrastructure in Gilbert's syndrome.Gut, 1975
- Apparent Michaelis constants for the metabolism of [ureyl-14C]tolbutamide by human liver microsomal preparationsBiochemical Pharmacology, 1972
- Studies of Y and Z, two hepatic cytoplasmic organic anion-binding proteins: effect of drugs, chemicals, hormones, and cholestasisJCI Insight, 1971
- Distribution of tolbutamide and chlorpropamide after administration to non-diabetic ratsEuropean Journal of Pharmacology, 1971
- Constitutional hepatic dysfunction (Gilbert's syndrome): A new definition based on kinetic studies with unconjugated radiobilirubinAmerican Journal Of Medicine, 1970
- Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anionsJCI Insight, 1969
- Hepatic Bilirubin UDP-Glucuronyl Transferase Activity in Liver Disease and Gilbert's SyndromeNew England Journal of Medicine, 1969
- Hepatic Aspects of Bilirubin MetabolismAnnual Review of Medicine, 1966
- A simple efficient liquid scintillator for counting aqueous solutions in a liquid scintillation counterAnalytical Biochemistry, 1960
- Über eine Möglichkeit zur colorimetrischen Bestimmung von N-(4-Methyl-benzolsulfonyl)-N′-butyl-Harnstoff in SerumJournal of Molecular Medicine, 1957