The Activity of Members of the UDP-Glucuronosyltransferase Subfamilies UGT1A and UGT2B is Impaired in Patients with Liver Cirrhosis

Abstract

Background and objective: The impact of liver cirrhosis on the activity of UDP-glucuronosyltransferases (UGTs) is currently not well characterized. We investigated the glucuronidation capacity and glucuronide accumulation in patients with liver cirrhosis.

Methods: We administered the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, midazolam) to patients with liver cirrhosis (n = 16 Child A, n = 15 Child B, n = 5 Child C) and n = 12 control subjects and obtained pharmacokinetic profiles of substrates and primary metabolites and their glucuronides.

Results: Caffeine and its metabolite paraxanthine were only slightly glucuronidated. The metabolic ratio (AUC_glucuronide/AUC_parent, MR) was not affected for caffeine but decreased by 60% for paraxanthine glucuronide formation in Child C patients. Efavirenz was not glucuronidated whereas 8-hydroxyefavirenz was efficiently glucuronidated. The MR of 8-hydroxyefavirenz-glucuronide formation increased three-fold in Child C patients and was negatively correlated with the glomerular filtration rate. Flurbiprofen and omeprazole were not glucuronidated. 4-Hydroxyflurbiprofen and 5-hydroxyomeprazole were both glucuronidated but the corresponding MRs for glucuronide formation were not affected by liver cirrhosis. Metoprolol, but not α-hydroxymetoprolol, was glucuronidated, and the MR for metoprolol-glucuronide formation dropped by 60% in Child C patients. Both midazolam and its metabolite 1'-hydroxymidazolam underwent glucuronidation, and the corresponding MRs for glucuronide formation dropped by approximately 80% in Child C patients. No relevant glucuronide accumulation occurred in patients with liver cirrhosis.

Conclusions: Detailed analysis revealed that liver cirrhosis may affect the activity of UGTs of the UGT1A and UGT2B subfamilies according to liver function. Clinically significant glucuronide accumulation did not occur in the population investigated.

Clinical trial registration: NCT03337945.

Fig. 1

Bland–Altman plots (difference plots) of plasma samples before and after deglucuronidation. Thirty-six patients with liver cirrhosis (n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis) and 12 matched control subjects were treated with the Basel phenotyping cocktail containing six substrates. Subjects abstained from caffeine ingestion for the 24 h preceding and during the study day. Serial blood samples were obtained and analyzed before and after deglucuronidation. The figure shows the difference between the concentrations after and before deglucuronidation of the substrates and their primary metabolites, which is plotted against their average (Bland–Altman plot). Negative values are plotted in red. The figure shows that caffeine, paraxanthine, metoprolol, midazolam, 8-hydroxyefavirenz, 4-hydroxyflurbiprofen, 5-hydroxyomeprazole, and 1′-hydroxymidazolam are partially glucuronidated

Fig. 2

Plasma concentration–time plots (1A–C) and area under the curve (AUC) and metabolic ratios (2A–C) of the glucuronides of the substrates of the Basel phenotyping cocktail showing significant glucuronidation. Thirty-six patients with liver cirrhosis (n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis) and 12 matched control subjects were treated with the Basel phenotyping cocktail containing six substrates. Serial blood samples were obtained, and the plasma concentration of the substrates determined before and after deglucuronidation. Glucuronide concentrations were calculated as the difference between the values after and before deglucuronidation. Values are shown as the mean ± standard error of the mean. h h

Fig. 3

Plasma concentration–time plots (1A–E) and area under the curve (AUC) and metabolic ratios (2A–E) of the glucuronides of the primary metabolites of the substrates of the Basel phenotyping cocktail showing significant glucuronidation. Thirty-six patients with liver cirrhosis (n = 16 patients with Child A cirrhosis, n = 15 patients with Child B cirrhosis, n = 5 patients with Child C cirrhosis) and 12 matched control subjects were treated with the Basel phenotyping cocktail containing six substrates. Serial blood samples were obtained, and the plasma concentration of the primary metabolites of the substrates determined before and after deglucuronidation. Glucuronide concentrations were calculated as the difference between the values after and before deglucuronidation. Values are shown as the mean ± standard error of the mean. h hours