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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.
Purpose:
While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use.
Methods:
FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T1 -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured.
Results:
Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts.
Conclusion:
Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models.
Insights
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.
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.
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