title: Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast-enhanced Magnetic Resonance Imaging.
abstract: To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established.
authors.affiliation: Preclinical and Translational Imaging, GlaxoSmithKline, King of Prussia, Pennsylvania, USA Laboratory Animal Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania, USA stephen.c.lenhard@GSK.com.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Lenhard
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Mally
authors.initials: M
authors.lastname: Lev
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Lindsey O
authors.initials: LO
authors.lastname: Webster
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Peterson
authors.affiliation: Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Goulbourne
authors.affiliation: Laboratory Animal Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miller
authors.affiliation: Preclinical and Translational Imaging, GlaxoSmithKline, King of Prussia, Pennsylvania, USA Laboratory Animal Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Beat M
authors.initials: BM
authors.lastname: Jucker
mesh_terms: D000638:Amiodarone / Q000633:toxicity; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010743:Phospholipids; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA; D000638:Amiodarone
keywords: amiodarone; cationic amphiphilic drug; gadoxetate contrast agent; hepatobiliary transporter function; magnetic resonance imaging; phospholipidosis