title: Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition.
abstract: Drug-induced liver injury (DILI) is a clinically important adverse drug reaction, which prevents the development of many otherwise safe and effective new drugs. Currently, there is a lack of sensitive and specific biomarkers that can be used to predict, assess and manage this toxicity. The aim of this work was to evaluate gadoxetate-enhanced MRI as a potential novel biomarker of hepatobiliary transporter inhibition in the rat. Initially, the volume fraction of extracellular space in the liver was determined using gadopentetate to enable an estimation of the gadoxetate concentration in hepatocytes. Using this information, a compartmental model was developed to characterise the pharmacokinetics of hepatic uptake and biliary excretion of gadoxetate. Subsequently, we explored the impact of an investigational hepatobiliary transporter inhibitor on the parameters of the model in vivo in rats. The investigational hepatobiliary transporter inhibitor reduced both the rate of uptake of gadoxetate into the hepatocyte, k1 , and the Michaelis-Menten constant, Vmax , characterising its excretion into bile, whereas KM values for biliary efflux were increased. These effects were dose dependent and correlated with effects on plasma chemistry markers of liver dysfunction, in particular bilirubin and bile acids. These results indicate that gadoxetate-enhanced MRI provides a novel functional biomarker of inhibition of transporter-mediated hepatic uptake and clearance in the rat. Since gadoxetate is used clinically, the technology has the potential to provide a translatable biomarker of drug-induced perturbation of hepatic transporters that may also be useful in humans to explore deleterious functional alterations caused by transporter inhibition.
authors.affiliation: Science and Validation, Personalised Healthcare and Biomarkers, AstraZeneca, Macclesfield, UK.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Ulloa
authors.forename: Simone
authors.initials: S
authors.lastname: Stahl
authors.forename: James
authors.initials: J
authors.lastname: Yates
authors.forename: Neil
authors.initials: N
authors.lastname: Woodhouse
authors.forename: J Gerry
authors.initials: JG
authors.lastname: Kenna
authors.forename: Huw B
authors.initials: HB
authors.lastname: Jones
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.forename: Paul D
authors.initials: PD
authors.lastname: Hockings
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism*; D003287:Contrast Media; D005110:Extracellular Space / Q000378:metabolism; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D003287:Contrast Media; D019786:Gadolinium DTPA; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C490548:Abcb11 protein, rat; C503999:SLCO1B1 protein, human; C073590:gadolinium ethoxybenzyl DTPA
keywords: DCE-MRI; DILI; drug-induced liver injury; hepatobiliary transporters; imaging biomarker; liver; pharmacokinetic model; safety biomarker
references.citation: Contrast Media Mol Imaging. 2009 Jan-Feb;4(1):1-23
references.pmid: 19156706
references.citation: Hepatology. 2006 Dec;44(6):1581-8
references.pmid: 17133470
references.citation: Radiology. 1996 Apr;199(1):177-83
references.pmid: 8633143
references.citation: Magn Reson Med. 2006 Mar;55(3):472-7
references.pmid: 16450339
references.citation: Drug Metab Pharmacokinet. 2009;24(1):37-52
references.pmid: 19252335
references.citation: J Hepatol. 2005 Aug;43(2):342-57
references.pmid: 15975683
references.citation: Biochim Biophys Acta. 2002 Mar 16;1586(2):129-45
references.pmid: 11959455
references.citation: Magn Reson Med. 2003 Sep;50(3):493-9
references.pmid: 12939756
references.citation: J Biol Chem. 1996 Mar 22;271(12):6702-7
references.pmid: 8636089
references.citation: Magn Reson Imaging. 2005 May;23(4):519-29
references.pmid: 15919597
references.citation: J Pharmacol Exp Ther. 1999 Jul;290(1):153-7
references.pmid: 10381771
references.citation: Biochim Biophys Acta. 2003 Jan 10;1609(1):1-18
references.pmid: 12507753
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17937-42
references.pmid: 19008355
references.citation: Gastroenterology. 2007 Jan;132(1):272-81
references.pmid: 17241877
references.citation: Radiology. 1995 Jun;195(3):785-92
references.pmid: 7754011
references.citation: Chem Biol Interact. 2004 Nov 20;150(2):179-87
references.pmid: 15535988
references.citation: Magn Reson Med. 2004 Apr;51(4):661-7
references.pmid: 15065237
references.citation: Arzneimittelforschung. 1993 Sep;43(9):1020-4
references.pmid: 8240452
references.citation: Hepatology. 2002 Jul;36(1):164-72
references.pmid: 12085361
references.citation: Magn Reson Med. 2007 Sep;58(3):463-72
references.pmid: 17763352
references.citation: Nat Rev Drug Discov. 2010 Mar;9(3):215-36
references.pmid: 20190787
references.citation: Magn Reson Med. 2005 Dec;54(6):1351-9
references.pmid: 16247739
references.citation: Radiology. 1994 Mar;190(3):753-8
references.pmid: 8115623
references.citation: J Cell Biol. 1977 Feb;72(2):441-55
references.pmid: 833203
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Abdom Imaging. 2012 Apr;37(2):164-79
references.pmid: 21516381
references.citation: J Magn Reson Imaging. 2010 Mar;31(3):571-8
references.pmid: 20187199
references.citation: Magn Reson Med. 2003 Dec;50(6):1151-69
references.pmid: 14648563
references.citation: Radiology. 1990 Jan;174(1):7-8
references.pmid: 2403685
references.citation: Xenobiotica. 2008 Jul;38(7-8):778-801
references.pmid: 18668430
references.citation: Drug Metab Pharmacokinet. 2003;18(1):16-22
references.pmid: 15618715
references.citation: Magn Reson Med. 2002 Jan;47(1):135-42
references.pmid: 11754452
references.citation: Magn Reson Med. 1991 Dec;22(2):233-7; discussion 242
references.pmid: 1812351
references.citation: Invest Radiol. 2005 Nov;40(11):715-24
references.pmid: 16230904
references.citation: Xenobiotica. 2010 Jan;40(1):24-37
references.pmid: 19919292
references.citation: Drug Saf. 2007;30(4):277-94
references.pmid: 17408305
references.citation: Radiology. 2005 Oct;237(1):89-98
references.pmid: 16126918
references.citation: J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S83-9
references.pmid: 15758665
references.citation: J Magn Reson Imaging. 2010 Feb;31(2):365-72
references.pmid: 20099350
references.citation: Magn Reson Med. 2008 Feb;59(2):326-35
references.pmid: 18228592
references.citation: Radiology. 1992 Apr;183(1):59-64
references.pmid: 1549695
references.citation: Magn Reson Med. 1999 Sep;42(3):467-78
references.pmid: 10467291
references.citation: Arzneimittelforschung. 1993 Aug;43(8):927-31
references.pmid: 8216456
references.citation: Am J Physiol. 1996 Feb;270(2 Pt 2):F326-31
references.pmid: 8779894
references.citation: Drug Metab Rev. 2010 Aug;42(3):402-36
references.pmid: 20082599
references.citation: Science. 1996 Feb 23;271(5252):1126-8
references.pmid: 8599091
references.citation: Expert Opin Drug Metab Toxicol. 2008 May;4(5):545-68
references.pmid: 18484914
references.citation: Magn Reson Imaging. 1989 Jul-Aug;7(4):411-6
references.pmid: 2682115
references.citation: Drug Metab Dispos. 2012 Jan;40(1):130-8
references.pmid: 21965623
references.citation: Drug Metab Rev. 2008;40(4):511-37
references.pmid: 18821100
references.citation: Annu Rev Pharmacol Toxicol. 2005;45:689-723
references.pmid: 15822193
references.citation: Clin Pharmacol Ther. 2001 Apr;69(4):223-31
references.pmid: 11309550
references.citation: AAPS J. 2006 Feb 03;8(1):E48-54
references.pmid: 16584133
references.citation: Drug Metab Rev. 2010 Aug;42(3):380-401
references.pmid: 20100011
references.citation: Expert Opin Drug Metab Toxicol. 2005 Oct;1(3):429-45
references.pmid: 16863454
references.citation: World J Gastroenterol. 2009 Apr 14;15(14):1677-89
references.pmid: 19360911
references.citation: Magn Reson Med. 1991 Feb;17(2):357-67
references.pmid: 2062210
references.citation: Hepatology. 1999 Aug;30(2):485-90
references.pmid: 10421658
references.citation: Toxicology. 2001 Oct 5;167(1):83-98
references.pmid: 11557132
references.citation: Clin Pharmacol Ther. 2011 Jun;89(6):806-15
references.pmid: 21544079
references.citation: Mol Pharm. 2007 Nov-Dec;4(6):895-910
references.pmid: 18001054
references.citation: Gastroenterology. 2000 Feb;118(2):422-30
references.pmid: 10648470
references.citation: Invest Radiol. 1992 Aug;27(8):612-9
references.pmid: 1428739
references.citation: Radiology. 2005 Feb;234(2):468-78
references.pmid: 15591431
references.citation: J Biol Chem. 1996 Jun 21;271(25):15091-8
references.pmid: 8662992
references.citation: Radiology. 1990 Jan;174(1):17-23
references.pmid: 2403679
references.citation: J Pharm Sci. 1993 Aug;82(8):799-803
references.pmid: 8377117
references.citation: J Hepatol. 1997;26 Suppl 1:31-5
references.pmid: 9138126
references.citation: Magn Reson Med. 2000 Oct;44(4):563-74
references.pmid: 11025512
references.citation: Korean J Radiol. 2004 Oct-Dec;5(4):231-9
references.pmid: 15637473
references.citation: Acad Radiol. 1996 Aug;3 Suppl 2:S232-4
references.pmid: 8796570
references.citation: J Magn Reson Imaging. 2011 Feb;33(2):409-16
references.pmid: 21274983
references.citation: Magn Reson Med. 2001 Apr;45(4):720-3
references.pmid: 11284003
references.citation: J Pharmacol Exp Ther. 2003 Feb;304(2):610-6
references.pmid: 12538813
references.citation: Invest Radiol. 2002 Dec;37(12):680-4
references.pmid: 12447001
references.citation: Invest Radiol. 1996 Mar;31(3):154-60
references.pmid: 8675423
references.citation: J Biol Chem. 2001 Mar 30;276(13):9626-30
references.pmid: 11134001
references.citation: AJR Am J Roentgenol. 2002 Jul;179(1):87-92
references.pmid: 12076911
references.citation: J Magn Reson Imaging. 2010 Feb;31(2):356-64
references.pmid: 20099349
references.citation: Hepatology. 1997 Dec;26(6):1667-77
references.pmid: 9398014
references.citation: Pharmacogenet Genomics. 2007 Jun;17(6):403-15
references.pmid: 17502832
references.citation: Gastroenterology. 1994 Jul;107(1):255-65
references.pmid: 8020669
references.citation: Eur Radiol. 2012 Mar;22(3):642-53
references.pmid: 21984449
references.citation: J Magn Reson Imaging. 1999 Sep;10(3):223-32
references.pmid: 10508281
references.citation: Radiology. 2011 Nov;261(2):394-403
references.pmid: 21828189
references.citation: Biochem J. 2003 May 1;371(Pt 3):897-905
references.pmid: 12568656