Chimeric mouse model for MRI contrast agent evaluation

• Published in: Magnetic resonance in medicine 2019-07, Vol.82 (1), p.387-394
• Main Authors: Mir, Faryal F., Tomaszewski, Ryan P., Shuboni‐Mulligan, Dorela D., Mallett, Christiane L., Hix, Jeremy M. L., Ether, Nicholas D., Shapiro, Erik M.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; chimera; Contrast agents; Contrast Media - administration & dosage; Contrast Media - analysis; Contrast Media - pharmacokinetics; Evaluation; Feces - chemistry; Gadolinium; Gadolinium DTPA - administration & dosage; Gadolinium DTPA - analysis; Gadolinium DTPA - pharmacokinetics; humanized model; Humans; Intravenous administration; Liver; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Meglumine - administration & dosage; Meglumine - analogs & derivatives; Meglumine - analysis; Meglumine - pharmacokinetics; Mice; Mice, Transgenic; MRI; OATP; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Organic anion transporting polypeptide; Organometallic Compounds - administration & dosage; Organometallic Compounds - analysis; Organometallic Compounds - pharmacokinetics; Polypeptides; preclinical; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Urine
• ISSN: 0740-3194; 1522-2594
• DOI: 10.1002/mrm.27730

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.