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Chimeric mouse model for MRI contrast agent evaluation.

Faryal F Mir1,2,3, Ryan P Tomaszewski1, Dorela D Shuboni-Mulligan1,2

  • 1Michigan State University, Department of Radiology, East Lansing, Michigan.

Magnetic Resonance in Medicine
|March 16, 2019
PubMed
Summary
This summary is machine-generated.

Chimeric mice expressing human liver transporters better predict MRI contrast agent clearance in humans than traditional rodent models. This improves the evaluation of new agents for clinical use.

Keywords:
MRIOATPchimeragadoliniumhumanized modelpreclinical

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Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Biomedical Imaging
  • Translational Research

Background:

  • Rodent models are crucial for evaluating MRI contrast agents but may not accurately reflect human organ clearance.
  • Differences in transporter expression between rodents and humans can lead to significant discrepancies in contrast agent pharmacokinetics.
  • Gadolinium-based contrast agents (GBCAs) require precise evaluation of their hepatic clearance for safe clinical application.

Purpose of the Study:

  • To assess the utility of chimeric mice expressing human organic anion-transporting polypeptides (OATPs) for evaluating MRI contrast agent hepatic clearance.
  • To compare the accuracy of chimeric mice versus wild-type rodents in predicting human contrast agent pharmacokinetics.
  • To determine if chimeric mice improve the preclinical screening of novel MRI contrast agents.

Main Methods:

  • Chimeric mice expressing human OATP1B1/1B3 and wild-type FVB mice were intravenously injected with hepatospecific (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific (Gd-DTPA) contrast agents.
  • Dynamic contrast-enhanced T1-weighted MRI was performed to quantify hepatic signal enhancement over time.
  • Gadolinium mass balance, fecal, and urinary elimination percentages were measured to assess clearance pathways.

Main Results:

  • Chimeric mice showed hepatic clearance of Gd-BOPTA that more closely mimicked human data compared to wild-type mice.
  • Gd-BOPTA hepatic signal enhancement was reduced by 78% in chimeric mice relative to wild-type.
  • Fecal elimination of Gd-BOPTA was significantly lower (32%) in chimeric mice than in wild-type (83%), aligning with human data.

Conclusions:

  • Chimeric mice expressing human OATPs provide a more accurate preclinical model for evaluating MRI contrast agent hepatic clearance than traditional wild-type rodents.
  • This improved model closely mimics human hepatic MRI signal enhancement and elimination patterns for agents like Gd-EOB-DTPA and Gd-BOPTA.
  • Chimeric mice represent a valuable tool for enhancing the screening and development of novel MRI contrast agents for clinical use.