title: Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Mark J
authors: MJ
authors: Canet
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Matthew D
authors: MD
authors: Merrell
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Rhiannon N
authors: RN
authors: Hardwick
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Amy M
authors: AM
authors: Bataille
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Sarah N
authors: SN
authors: Campion
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Daniel W
authors: DW
authors: Ferreira
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Stavra A
authors: SA
authors: Xanthakos
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Jose E
authors: JE
authors: Manautou
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: H Hesham
authors: HH
authors: A-Kader
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.).
authors: Robert P
authors: RP
authors: Erickson
authors: Departments of Pharmacology and Toxicology (M.J.C., M.D.M., R.N.H., N.J.C.) and Pediatrics (H.A.K., R.P.E.), University of Arizona, Tucson, Arizona; School of Pharmacy, University of Connecticut, Storrs, Connecticut (A.M.B., D.W.F., J.E.M.); Drug Safety Research and Development, Pfizer, Inc., New York, New York (S.N.C.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (S.A.X.) cherrington@pharmacy.arizona.edu.
authors: Nathan J
authors: NJ
authors: Cherrington
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000293:Adolescent; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001648:Bile Canaliculi / Q000378:metabolism / Q000473:pathology; D001711:Biotransformation; D002648:Child; D015331:Cohort Studies; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000652:urine; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D010865:Pilot Projects; D021381:Protein Transport; D015854:Up-Regulation
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3; C037386:acetaminophen glucuronide; C045667:acetaminophen sulfate ester