Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis

Clin Pharmacol Ther. 2015 Apr;97(4):419-27. doi: 10.1002/cpt.66. Epub 2015 Mar 15.


The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax ) and area under the concentration-time curve (AUC0-last ) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225 nM and 58.8 vs. 37.2 µM*min, respectively; P ≤ 0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P < 0.001). Fasting serum glycocholate, taurocholate, and total bile acid concentrations were associated with NASH severity (P < 0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / metabolism*
  • Analgesics, Opioid / pharmacokinetics
  • Area Under Curve
  • Bile Acids and Salts / metabolism*
  • Cohort Studies
  • Female
  • Humans
  • Insulin Resistance
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism
  • Male
  • Middle Aged
  • Morphine Derivatives / metabolism*
  • Morphine Derivatives / pharmacokinetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology


  • Analgesics, Opioid
  • Bile Acids and Salts
  • Morphine Derivatives
  • morphine-6-glucuronide
  • morphine-3-glucuronide