Jose Ulloa1, Simone Stahl2,
Carsten Liess1, Jonathan Bright3, Angela McDermott2,
Neil Woodhouse1, Jane Halliday1, Arvind Parmar1,
Guy Healing2, Gerry Kenna2, Andrew Holmes1,
Herv Barjat1, John Waterton1, Paul Hockings1
1Translational Sciences, Astrazeneca,
Macclesfield, Cheshire, United Kingdom; 2Safety Assessment,
Astrazeneca, Macclesfield, Cheshire, United Kingdom; 3Discovery
Statistics, Astrazeneca, Macclesfield, Cheshire, United Kingdom
Cholestasis
is an important mechanism that can result in drug induced liver injury, a
recurrent cause of attrition of new drug candidates. In rats, transporters
Oatp1 and Mrp2 mediate liver uptake and clearance of gadoxetate, a
hepatobiliary contrast agent used to characterise focal liver lesions.
Estradiol-17β D-glucuronide (E217G) induces acute but
transient cholestasis in rats through impairment of Mrp2 and Bsep function.
The aim of this work was to assess whether characterisation of the kinetics
of gadoxetate excretion can detect transient cholestasis induced by E217G.
Results suggest this method can be used to investigate inhibition of
transporters mediating biliary excretion.