title: Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging: Monitoring Transporter-Mediated Processes in Healthy Volunteers.
abstract: The objective of this study was to use noninvasive dynamic contrast-enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers.
  
  
  
  Ten healthy volunteers (age range, 18-29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast-enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time.
  
  
  
  Eight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 ± 0.05 and 0.017 ± 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 ± 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: ±0.02/min, kef: ±0.004/min) was lower compared with the individual variability (repeatability; ki: ±0.06/min, kef: ±0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes.
  
  
  
  This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions.
authors.affiliation: From the *Centre for Imaging Sciences, and †Manchester Pharmacy School, University of Manchester, Manchester; ‡AstraZeneca Research and Development-DMPK Innovative Medicines, and §AstraZeneca Personalised Healthcare and Biomarkers iMED, Melbourn, Royston, United Kingdom.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Georgiou
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Penny
authors.forename: Glynis
authors.initials: G
authors.lastname: Nicholls
authors.forename: Neil
authors.initials: N
authors.lastname: Woodhouse
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Blé
authors.forename: Penny L
authors.initials: PL
authors.lastname: Hubbard Cristinacce
authors.forename: Josephine H
authors.initials: JH
authors.lastname: Naish
mesh_terms: D000293:Adolescent; D000328:Adult; D003287:Contrast Media; D005069:Evaluation Studies as Topic; D005260:Female; D019786:Gadolinium DTPA; D064368:Healthy Volunteers; D006801:Humans; D007089:Image Enhancement / Q000379:methods*; D008099:Liver / Q000000981:diagnostic imaging / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D012016:Reference Values; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA