title: Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis.
abstract: 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.
authors: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: B C
authors: BC
authors: Ferslew
authors: C K
authors: CK
authors: Johnston
authors: E
authors: E
authors: Tsakalozou
authors: A S
authors: AS
authors: Bridges
authors: M F
authors: MF
authors: Paine
authors: W
authors: W
authors: Jia
authors: P W
authors: PW
authors: Stewart
authors: A S
authors: AS
authors: Barritt
authors: K L R
authors: KL
authors: Brouwer
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000378:metabolism* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001647:Bile Acids and Salts / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009022:Morphine Derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; D001647:Bile Acids and Salts; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; C018108:morphine-3-glucuronide